Organic compounds and their uses

ABSTRACT

The present application describes organic compounds that are useful for the treatment, prevention and/or amelioration of human diseases.

BACKGROUND

Hepatitis C virus (HCV) is a (+)-sense single-stranded RNA virus thathas been implicated as the major causative agent in non-A, non-Bhepatitis (NANBH), particularly in blood-associated NANBH (BB-NANBH).NANBH is to be distinguished from other types of viral-induced liverdisease, such as hepatitis A virus (HAV), hepatitis B virus (HBV), deltahepatitis virus (HDV), cytomegalovirus (CMV) and Epstein-Barr virus(EBV), as well as from other forms of liver disease such as alcoholismand primary biliar cirrhosis.

Recently, an HCV protease necessary for polypeptide processing and viralreplication has been identified, cloned and expressed. (See, e.g., U.S.Pat. No. 5,712,145). This approximately 3000 amino acid polyproteincontains, from the amino terminus to the carboxy terminus, anucleocapsid protein (C), envelope proteins (E1 and E2) and severalnon-structural proteins (NS1, 2, 3, 4a, 5a and 5b). NS3 is anapproximately 68 kda protein, encoded by approximately 1893 nucleotidesof the HCV genome, and has two distinct domains: (a) a serine proteasedomain consisting of approximately 200 of the N-terminal amino acids;and (b) an RNA-dependent ATPase domain at the C-terminus of the protein.The NS3 protease is considered a member of the chymotrypsin familybecause of similarities in protein sequence, overall three-dimensionalstructure and mechanism of catalysis. The HCV NS3 serine protease isresponsible for proteolysis of the polypeptide (polyprotein) at theNS3/NS4a, NS4a/NS4b, NS4b/NS5a and NS5a/NS5b junctions and is thusresponsible for generating four viral proteins during viral replication.This has made the HCV NS3 serine protease an attractive target forantiviral chemotherapy.

It has been determined that the NS4a protein, an approximately 6 kdapolypeptide, is a co-factor for the serine protease activity of NS3.Autocleavage of the NS3/NS4a junction by the NS3/NS4a serine proteaseoccurs intramolecularly (i.e., cis) while the other cleavage sites areprocessed intermolecularly (i.e., trans).

HCV has been implicated in cirrhosis of the liver and in induction ofhepatocellular carcinoma. The prognosis for patients suffering from HCVinfection is currently poor. HCV infection is more difficult to treatthan other forms of hepatitis due to the lack of immunity or remissionassociated with HCV infection. Current data indicates a less than 50%survival rate at four years post cirrhosis diagnosis. Patients diagnosedwith localized resectable hepatocellular carcinoma have a five-yearsurvival rate of 10-30%, whereas those with localized unresectablehepatocellular carcinoma have a five-year survival rate of less than 1%.

Current therapies for hepatitis C include interferon-α (INF_(α)) andcombination therapy with ribavirin and interferon. See, e.g., Beremgueret al. (1998) Proc. Assoc. Am. Physicians 110(2):98-112. These therapiessuffer from a low sustained response rate and frequent side effects.See, e.g., Hoofnagle et al. (1997) N. Engl. J. Med. 336:347. Currently,no vaccine is available for HCV infection.

SUMMARY OF THE INVENTION

There remains a need for new treatments and therapies for HCV infection,as well as HCV-associated disorders. There is also a need for compoundsuseful in the treatment or prevention or amelioration of one or moresymptoms of HCV, as well as a need for methods of treatment orprevention or amelioration of one or more symptoms of HCV. Furthermore,there is a need for methods for modulating the activity of HCV-serineproteases, particularly the HCV NS3/NS4a serine protease, using thecompounds provided herein.

In one aspect, the invention provides compounds of Formula I:

and pharmaceutically acceptable salts and stereoisomers thereof.

In another aspect, the invention provides compounds of Formula III:

and pharmaceutically acceptable salts and stereoisomers thereof whereinX or R₆ and R₇, taken in combination, comprise a spirocyclic ring systemwhich is spiro to the ring comprising the X variable.

In one embodiment, the invention provides a method of treating anHCV-associated disorder comprising administering to a subject in needthereof a pharmaceutically acceptable amount of a compound of theinvention, such that the HCV-associated disorder is treated.

In another embodiment, the invention provides a method of treating anHIV infection comprising administering to a subject in need thereof apharmaceutically acceptable amount of a compound of the invention.

In still another embodiment, the invention provides a method oftreating, inhibiting or preventing the activity of HCV in a subject inneed thereof, comprising administering to the subject a pharmaceuticallyacceptable amount of a compound of the invention. In one embodiment, thecompounds of the invention inhibit the activity of the NS2 protease, theNS3 protease, the NS3 helicase, the NS5a protein, and/or the NS5bpolymerase. In another embodiment, the interaction between the NS3protease and NS4A cofactor is disrupted. In yet another embodiment, thecompounds of the invention prevent or alter the severing of one or moreof the NS4A-NS4B, NS4B-NS5A and NS5A-NS5B junctions of the HCV. Inanother embodiment, the invention provides a method of inhibiting theactivity of a serine protease, comprising the step of contacting saidserine protease with a compound of the invention. In another embodiment,the invention provides a method of treating, inhibiting or preventingthe activity of HCV in a subject in need thereof, comprisingadministering to the subject a pharmaceutically acceptable amount of acompound of the invention, wherein the compound interacts with anytarget in the HCV life cycle. In one embodiment, the target of the HCVlife cycle is selected from the group consisting of NS2 protease, NS3protease, NS3 helicase, NS5a protein and NS5b polymerase.

In another embodiment, the invention provides a method of decreasing theHCV RNA load in a subject in need thereof comprising administering tothe subject a pharmaceutically acceptable amount of a compound of theinvention.

In another embodiment, the compounds of the invention exhibit HCVprotease activity. In one embodiment, the compounds are an HCV NS3-4Aprotease inhibitor.

In another embodiment, the invention provides a method of treating anHCV-associated disorder in a subject, comprising administering to asubject in need thereof a pharmaceutically acceptable amount of acompound of the invention, and a pharmaceutically acceptable carrier,such that the HCV-associated disorder is treated.

In still another embodiment, the invention provides a method of treatingan HCV-associated disorder comprising administering to a subject in needthereof a pharmaceutically effective amount of a compound of theinvention, in combination with a pharmaceutically effective amount of anadditional HCV-modulating compound, such as interferon or derivatizedinterferon, or a cytochrome P450 monooxygenase inhibitor, such that theHCV-associated disorder is treated. In one embodiment, the additionalHCV-modulating compound is selected from the group consisting of Sch503034 and VX-950.

In another embodiment, the invention provides a method of inhibitinghepatitis C virus replication in a cell, comprising contacting said cellwith a compound of the invention.

In yet another embodiment, the invention provides a packagedHCV-associated disorder treatment, comprising an HCV-modulating compoundof the invention, packaged with instructions for using an effectiveamount of the HCV-modulating compound to treat an HCV-associateddisorder.

In certain embodiments, the HCV-associated disorder is selected from thegroup consisting of HCV infection, liver cirrhosis, chronic liverdisease, hepatocellular carcinoma, cryoglobulinaemia, non-Hodgkin'slymphoma, and a suppressed innate intracellular immune response.

In another embodiment, the invention provides a method of treating HCVinfection, liver cirrhosis, chronic liver disease, hepatocellularcarcinoma, cryoglobulinaemia, non-Hodgkin's lymphoma, and/or asuppressed innate intracellular immune response in subject in needthereof comprising administering to the subject a pharmaceuticallyacceptable amount of a compound of the invention.

In one embodiment, the HCV to be treated is selected of any HCVgenotype. In another embodiment, the HCV is selected from HCV genotype1, 2 and/or 3.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to compounds, e.g., peptide compounds, andintermediates thereto, as well as pharmaceutical compositions containingthe compounds for use in treatment of HCV infection. This invention isalso directed to the compounds of the invention or compositions thereofas protease inhibitors, particularly as serine protease inhibitors, andmore particularly as HCV NS3 protease inhibitors. The compounds areparticularly useful in interfering with the life cycle of the hepatitisC virus and in treating or preventing an HCV infection or physiologicalconditions associated therewith. The present invention is also directedto methods of combination therapy for inhibiting HCV replication incells, or for treating or preventing an HCV infection in patients usingthe compounds of the invention or pharmaceutical compositions, or kitsthereof.

In one aspect, the compounds of the invention are of Formula I:

and pharmaceutically acceptable salts and stereoisomers thereof;wherein

y is 0 or 1;

n is 0, 1 or 2;

R¹⁴ is C(O) or SO₂;

R¹, R², W, R¹³ and V are each, independently, selected from hydrogen orfrom the group consisting of alkyl, alkyl-aryl, heteroalkyl,heterocyclyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl,alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy,cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkylamino, mono- anddi-alkylcarboxamide, arylalkyloxy and heterocyclylamino; each of whichmay be further independently substituted one or more times with X¹ andX² (or more preferably, each of which may be further substituted with 1,2, 3, 4, or 5 residues independently selected from X¹ and X²); whereinX¹ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, aralkyl, aryloxy,arylthio, arylheteroaryl, heteroaryl, heterocyclylamino,alkylheteroaryl, or heteroaralkyl; wherein X¹ can be independentlysubstituted with one or more X² moieties (or more preferably with 1, 2,3, 4, or 5 X² moieties) which can be the same or different and areindependently selected; wherein X² is hydroxy, oxo, alkyl, cycloalkyl,spirocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy,thio, alkylthio, amino, mono- and di-alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyl,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro;wherein each X² residue selected to be alkyl, alkoxy, and aryl can beunsubstituted or optionally independently substituted with one or moremoieties (or more preferably with 1, 2, 3, 4, or 5 moieties) which canbe the same or different and are independently selected from alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,heterocyclylalkyl, aryl, alkylaryl, aralkyl, arylheteroaryl, heteroaryl,heterocyclylamino, alkylheteroaryl and heteroaralkyl;

W is also selected from the group consisting of C(O)—C(O)H,C(═N—O—R₂₄)—C(O)-amine, C(O)—C(O)-amine, C(O)NR₂₄S(O)_(p)R₂₄,C(O)NR₂₄S(O)_(p)N(R₂₄)₂ and C(O)—[C(O)]_(a)-heterocycle, wherein theheterocycle may be independently substituted one or more times (orpreferably between one and five times) with aryl, C₁₋₄-alkyl, C₁₋₄-alkylsubstituted by one or more halogen atoms, and C₃₋₆-cycloalkyl, wherein ais 0 or 1, wherein each R₂₄ is independently selected from hydrogen orfrom the group consisting of C₁₋₄-alkyl, C₃₋₆-cycloalkylC₀₋₄alkyl,substituted or unsubstituted aryl and substituted or unsubstitutedheterocycle, each of which may be independently substituted one or moretimes (or preferably between one and five times) with a halogen atom orC₁₋₄-alkyl;

V is also selected from the group consisting of -Q¹-Q², wherein Q¹ isabsent, C(O), N(H), N(C₁₋₄-alkyl), C═N(CN), C═N(SO₂CH₃),C═N—COH—C₁₋₄-alkyl, or C═N—COH, and Q² is hydrogen or is selected fromthe group consisting of C₁₋₄-alkyl, O—C₁₋₄-alkyl, NH₂, N(H)—C₁₋₄-alkyl,N(C₁₋₄-alkyl)₂, SO₂-aryl, SO₂—C₁₋₄-alkyl, C₃₋₆-cycloalkyl-C₀₋₄-alkyl,aryl, heteroaryl and heterocycle, each of which may be independentlysubstituted one or more times with a halogen atom, C₁₋₄-alkyl,C₁₋₄-alkyl substituted by one or more halogen atoms, or C₃₋₆-cycloalkyl;

or R¹ and R² may together form a 3, 4, 5, 6 or 7-membered ring that isaromatic or non-aromatic and may contain one or more heteroatoms,wherein the ring may be further substituted one or more times (orpreferably between one and five times);

R³ is selected from the group consisting of hydrogen, C₁₋₄-alkyl andC₃₋₆-cycloalkylC₀₋₄alkyl;

X is O, S, N, NR⁵, CR⁵ or CR⁵R^(5a);

R⁴ is selected from hydrogen or from the group consisting of C₁₋₄-alkyl,C₃₋₆-cycloalkyl, aryl, heterocycle and heteroaryl, each of which may beindependently substituted one or more times (or preferably between oneand five times) with a halogen atom or C₁₋₄-alkyl;

R⁵ is selected from hydrogen or oxo or from the group consisting ofhydroxyl, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₃₋₈-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl, heterocycle-C₀₋₄-alkyl,heteroaryl-C₀₋₄-alkyl, C₃₋₈-cycloalkyloxy, aryloxy, and heteroaryloxyeach of which may be independently substituted one or more times (orpreferably between one and five times) with a halogen atom, aryl,trihalomethyl, or C₁₋₄-alkyl;

R^(5a) is selected from the group consisting of hydrogen, hydroxyl,C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl-C₀₋₄-alkyl,aryl-C₀₋₄-alkyl and heteroaryl-C₀₋₄-alkyl,

or R⁴ and R⁵ may together form a fused dimethyl cyclopropyl ring, afused cyclopentane ring, a fused phenyl ring or a fused pyridyl ring,each of which may be substituted with a halogen atom, aryl,trihalomethyl, or C₁₋₄-alkyl;

or R⁵ and R⁶ may together form a fused dimethyl cyclopropyl ring, afused cyclopentane ring, a fused phenyl ring or a fused pyridyl ring,each of which may be substituted with a halogen atom, aryl,trihalomethyl, or C₁₋₄-alkyl;

or R⁵ and R^(5a) may together form a spirocyclic ring having between 3and 7 ring atoms and having 0, 1, or 2 ring heteroatoms, which isoptionally substituted by 0-4 substituents selected from cyano, halogen,hydroxyl, amino, thiol, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₁₋₈-alkoxy-C₀₋₄alkyl, C₁₋₈-haloalkyl, C₂₋₈-haloalkenyl,C₂₋₈-haloalkynyl, C₁₋₈-haloalkoxy, C₁₋₈-alkylthio, C₁₋₈-alkylsulfonyl,C₁₋₈-alkylsulfoxy, C₁₋₈-alkanoyl, C₁₋₈-alkoxycarbonyl,C₃₋₇-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl,COOH, C(O)NH₂, mono- and di-C₁₋₄-alkyl-carboxamide, mono- anddi-C₁₋₄-alkyl-amino-C₀₋₄alkyl, SO₃H, SO₂NH₂, and mono- anddi-C₁₋₄-alkylsulfonamide, or two of said 0-4 substituents taken togetherform a fused or spirocyclic 3 to 7 membered ring having 0, 1 or 2 ringheteroatoms selected from N, O and S, which fused or spirocyclic ringhas 0 to 2 independently selected substituents selected from cyano,halogen, hydroxyl, amino, thiol, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₁₋₈-alkoxy-C₀₋₄alkyl, C₁₋₈-haloalkyl, C₂₋₈-haloalkenyl,C₂₋₈-haloalkynyl, C₁₋₈-haloalkoxy, C₁₋₈-alkylthio, C₁₋₈-alkylsulfonyl,C₁₋₈-alkylsulfoxy, C₁₋₈-alkanoyl, C₁₋₈-alkoxycarbonyl,C₃₋₇-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl,COOH, C(O)NH₂, mono- and di-C₁₋₄-alkyl-carboxamide, mono- anddi-C₁₋₄-alkyl-amino-C₀₋₄alkyl, SO₃H, SO₂NH₂, and mono- anddi-C₁₋₄-alkylsulfonamide;

R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each, independently, selected fromthe group consisting of hydrogen, C₁₋₄-alkyl andC₃₋₆-cycloalkylC₀₋₄alkyl;

or R⁶ and R⁷ may together form a spirocyclic ring having between 3 and 7ring atoms and having 0, 1, or 2 ring heteroatoms, which is optionallysubstituted by 0-4 substituents selected from cyano, halogen, hydroxyl,amino, thiol, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₁₋₈-alkoxy-C₀₋₄alkyl, C₁₋₈-haloalkyl, C₂₋₈-haloalkenyl,C₂₋₈-haloalkynyl, C₁₋₈-haloalkoxy, C₁₋₈-alkylthio, C₁₋₈-alkylsulfonyl,C₁₋₈-alkylsulfoxy, C₁₋₈-alkanoyl, C₁₋₈-alkoxycarbonyl,C₃₋₇-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl,COOH, C(O)NH₂, mono- and di-C₁₋₄-alkyl-carboxamide, mono- anddi-C₁₋₄-alkyl-amino-C₀₋₄alkyl, SO₃H, SO₂NH₂, and mono- anddi-C₁₋₄-alkylsulfonamide, or two substituents taken together form afused or spirocyclic 3 to 7 membered ring having 0, 1 or 2 ringheteroatoms selected from N, O and S, which fused or spirocyclic ringhas 0 to 2 independently selected substituents selected from halogen,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, mono- and di-C₁₋₄-alkylamino, mono-and di-C₁₋₄-alkyl-carboxamide, C₁₋₄-alkoxycarbonyl, and phenyl;

or R³ and W may together form a 3, 4, 5, 6 or 7-membered ring that isaromatic or non-aromatic and may contain one or more heteroatoms,wherein the ring may be further substituted one or more times (orpreferably between one and five times); and

or when y is 0, R¹⁰ and V may together form a 3, 4, 5, 6 or 7-memberedring that is aromatic or non-aromatic and may contain one or moreheteroatoms, wherein the ring may be further substituted one or moretimes (or preferably between one and five times).

In another aspect, the compounds of the invention are of Formula III:

and pharmaceutically acceptable salts and stereoisomers thereof;wherein

y is 0 or 1;

n is 0, 1 or 2;

R¹⁴ is C(O) or SO₂;

R¹, R², W, R¹³ and V are each, independently, selected from hydrogen orfrom the group consisting of alkyl, alkyl-aryl, heteroalkyl,heterocyclyl, heteroaryl, aryl-heteroaryl, alkyl-heteroaryl, cycloalkyl,alkyloxy, alkyl-aryloxy, aryloxy, heteroaryloxy, heterocyclyloxy,cycloalkyloxy, amino, alkylamino, arylamino, alkyl-arylamino, arylamino,heteroarylamino, cycloalkylamino, carboxyalkylamino, mono- anddi-alkylcarboxamide, aralkyloxy and heterocyclylamino; each of which maybe further independently substituted one or more times with X¹ and X²(or more preferably, each of which may be further substituted with 1, 2,3, 4, or 5 residues independently selected from X¹ and X²); wherein X¹is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,heterocyclylalkyl, aryl, alkylaryl, aralkyl, aryloxy, arylthio,arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl, orheteroaralkyl; wherein X¹ can be independently substituted with one ormore X² moieties (or more preferably with 1, 2, 3, 4, or 5 X² moieties)which can be the same or different and are independently selected;wherein X² is hydroxy, oxo, alkyl, cycloalkyl, spirocycloalkyl,heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, thio, alkylthio,amino, mono- and di-alkylamino, arylamino, alkylsulfonyl, arylsulfonyl,alkylsulfonamido, arylsulfonamido, carboxy, carbalkoxy, carboxamido,alkoxycarbonylamino, alkoxycarbonyl, alkoxycarbonyloxy, alkylureido,arylureido, halogen, cyano, or nitro; wherein each X² residue selectedto be alkyl, alkoxy, and aryl can be unsubstituted or optionallyindependently substituted with one or more moieties (or more preferablywith 1, 2, 3, 4, or 5 moieties) which can be the same or different andare independently selected from alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkyl-alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl,aralkyl, arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryland heteroaralkyl;

W is also selected from the group consisting of C(O)OH, C(O)OR₂₄,C(O)-amine, P(O)(OR₂₄)₂, C(O)—C(O)OH, C(═N—O—R₂₄)—C(O)-amine,C(O)NHS(O)₂R₂₄, C(O)NHS(O)₂N(R₂₄)₂, C(O)—C(O)-amine, CONHSO₂-amine andC(O)-[C(O)]_(a)-heterocycle, wherein the heterocycle may be substitutedor unsubstituted, wherein a is 0 or 1, wherein each R₂₄ is independentlyselected from the group consisting of hydrogen, halogen, hydroxyl,formyl, carboxylate, amide, amino, substituted orunsubstituted-C₁₋₄-alkyl, substituted or unsubstituted-C₁₋₄-alkoxy,substituted or unsubstituted-C₁₋₄-alkanoyl, substituted orunsubstituted-C₁₋₄-alkoxycarbonyl, substituted orunsubstituted-C₁₋₄-alkanoyloxy, substituted or unsubstituted mono- anddi-C₁₋₄-alkylamino, substituted orunsubstituted-C₃₋₆cycloalkyl-C₀₋₄alkyl, substituted or unsubstitutedaryl-C₀₋₄alkyl, and substituted or unsubstituted heterocycle-C₀₋₄alkyl;

V is also selected from the group consisting of -Q¹-Q², wherein Q¹ isabsent, C(O), N(H), N(C₁₋₄-alkyl), C═N(CN), C═N(SO₂CH₃),C═N—COH—C₁₋₄-alkyl, or C═N—COH, and Q² is hydrogen or is selected fromthe group consisting of C₁₋₄-alkyl, O—C₁₋₄-alkyl, NH₂, N(H)—C₁₋₄-alkyl,N(C₁₋₄-alkyl)₂, SO₂-aryl, SO₂—C₁₋₄-alkyl, C₃₋₆-cycloalkyl-C₀₋₄-alkyl,aryl, heteroaryl and heterocycle, each of which may be independentlysubstituted one or more times with a halogen atom, C₁₋₄-alkyl,C₁₋₄-alkyl substituted by one or more halogen atoms, or C₃₋₆-cycloalkyl;

or R¹ and R² may together form a 3, 4, 5, 6 or 7-membered ring that isaromatic or non-aromatic and may contain one or more heteroatoms,wherein the ring may be further substituted one or more times (orpreferably between one and five times);

R³ is selected from the group consisting of hydrogen, C₁₋₄-alkyl andC₃₋₆-cycloalkylC₀₋₄alkyl;

X is CR⁵R^(5a);

R⁴ represents 0-4 substituents, each of which is independently selectedfrom hydrogen or from the group consisting of C₁₋₄-alkyl,C₃₋₆-cycloalkyl, aryl, heterocycle and heteroaryl, each of which may beindependently substituted one or more times (or preferably between oneand five times) with a halogen atom or C₁₋₄-alkyl;

R⁵ is selected from hydrogen or oxo or the group consisting of hydroxyl,C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl-C₀₋₄-alkyl,aryl-C₀₋₄-alkyl, heterocycle-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl,C₃₋₈-cycloalkyloxy, aryloxy, and heteroaryloxy each of which may beindependently substituted one or more times (or preferably between oneand five times) with a halogen atom, aryl, trihalomethyl, or C₁₋₄-alkyl;

R^(5a) is selected from the group consisting of hydrogen, hydroxyl,C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl-C₀₋₄-alkyl,aryl-C₀₋₄-alkyl and heteroaryl-C₀₋₄-alkyl,

or R⁴ and R⁵ may together form a fused dimethyl cyclopropyl ring, afused cyclopentane ring, a fused phenyl ring or a fused pyridyl ring,each of which may be substituted with a halogen atom, aryl,trihalomethyl, or C₁₋₄-alkyl;

or R⁵ and R^(5a) may together form a spirocyclic ring having between 3and 7 ring atoms and having 0, 1, or 2 ring heteroatoms, which isoptionally substituted by 0-4 substituents selected from cyano, halogen,hydroxyl, amino, thiol, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₁₋₈-alkoxy-C₀₋₄alkyl, C₁₋₈-haloalkyl, C₂₋₈-haloalkenyl,C₂₋₈-haloalkynyl, C₁₋₈-haloalkoxy, C₁₋₈-alkylthio, C₁₋₈-alkylsulfonyl,C₁₋₈-alkylsulfoxy, C₁₋₈-alkanoyl, C₁₋₈-alkoxycarbonyl,C₃₋₇-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl,COOH, C(O)NH₂, mono- and di-C₁₋₄-alkyl-carboxamide, mono- anddi-C₁₋₄-alkyl-amino-C₀₋₄alkyl, SO₃H, SO₂NH₂, and mono- anddi-C₁₋₄-alkylsulfonamide, or two of said 0-4 substitutents takentogether form a fused or spirocyclic 3 to 7 membered ring having 0, 1 or2 ring heteroatoms selected from N, O and S, which fused or spirocyclicring has 0 to 2 independently selected substituents selected from cyano,halogen, hydroxyl, amino, thiol, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₁₋₈-alkoxy-C₀₋₄alkyl, C₁₋₈-haloalkyl, C₂₋₈-haloalkenyl,C₂₋₈-haloalkynyl, C₁₋₈-haloalkoxy, C₁₋₈-alkylthio, C₁₋₈-alkylsulfonyl,C₁₋₈-alkylsulfoxy, C₁₋₈-alkanoyl, C₁₋₈-alkoxycarbonyl,C₃₋₇-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl,COOH, C(O)NH₂, mono- and di-C₁₋₄-alkyl-carboxamide, mono- anddi-C₁₋₄-alkyl-amino-C₀₋₄alkyl, SO₃H, SO₂NH₂, and mono- anddi-C₁₋₄-alkylsulfonamide;

R⁶ and R⁷ are each, independently, selected from the group consisting ofhydroxy, amino, C₁₋₄alkyl, C₁₋₄alkoxy, and mono- and di-C₁₋₄alkylamino,and C₃₋₆cycloalkylC₀₋₄-alkyl;

R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each, independently, selected from thegroup consisting of hydrogen, C₁₋₄-alkyl and C₃₋₆-cycloalkylC₀₋₄alkyl;

or R⁶ and R⁷ may together form a spirocyclic ring having between 3 and 7ring atoms and having 0, 1, or 2 ring heteroatoms, which is optionallysubstituted by 0-4 substituents selected from cyano, halogen, hydroxyl,amino, thiol, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₁₋₈-alkoxy-C₀₋₄alkyl, C₁₋₈-haloalkyl, C₂₋₈-haloalkenyl,C₂₋₈-haloalkynyl, C₁₋₈-haloalkoxy, C₁₋₈-alkylthio, C₁₋₈-alkylsulfonyl,C₁₋₈-alkylsulfoxy, C₁₋₈-alkanoyl, C₁₋₈-alkoxycarbonyl,C₃₋₇-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl,COOH, C(O)NH₂, mono- and di-C₁₋₄-alkyl-carboxamide, mono- anddi-C₁₋₄-alkyl-amino-C₀₋₄alkyl, SO₃H, SO₂NH₂, and mono- anddi-C₁₋₄-alkylsulfonamide, or two substituents taken together form afused or spirocyclic 3 to 7 membered ring having 0, 1 or 2 ringheteroatoms selected from N, O and S, which fused or spirocyclic ringhas 0 to 2 independently selected substituents selected from halogen,C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, mono- and di-C₁₋₄-alkylamino, mono-and di-C₁₋₄-alkyl-carboxamide, C₁₋₄-alkoxycarbonyl, and phenyl;

wherein at least one of R⁵ and R^(5a) or R⁶ and R⁷, taken incombination, form a spirocyclic ring having at least one spirocyclicring substituent;

or R³ and W may together form a 3, 4, 5, 6 or 7-membered ring that isaromatic or non-aromatic and may contain one or more heteroatoms,wherein the ring may be further substituted one or more times (orpreferably between one and five times); and

or when y is 0, R¹⁰ and V may together form a 3, 4, 5, 6 or 7-memberedring that is aromatic or non-aromatic and may contain one or moreheteroatoms, wherein the ring may be further substituted one or moretimes (or preferably between one and five times).

In one embodiment of formula I, y is 0 or 1;

n is 0 or 1;

R¹⁴ is C(O) or SO₂

R¹ is selected from the group consisting of H and C₁₋₄-alkyl;

R² is selected from the group consisting of C₁₋₄-alkyl, C(O)C₁₋₄-alkyl,C(O)OC₁₋₄-alkyl, and C₃₋₆-cycloalkylC₀₋₄alkyl;

or R¹ and R² together form a cyclopropane ring;

W is also selected from the group consisting of C(O)—C(O)H,C(═N—O—R₂₄)—C(O)-amine, C(O)—C(O)-amine and C(O)-[C(O)]_(a) heterocycle,wherein the heterocycle may be independently substituted one or moretimes (or preferably between one and five times) with aryl, C₁₋₄-alkyl,C₁₋₄-alkyl substituted by one or more halogen atoms, andC₃₋₆-cycloalkyl, wherein a is 0 or 1, wherein each R₂₄ is independentlyselected from hydrogen or from the group consisting of C₁₋₄-alkyl,C₃₋₆-cycloalkylC₀₋₄alkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heterocycle, each of which may beindependently substituted one or more times (or preferably between oneand five times) with a halogen atom or C₁₋₄-alkyl;

R³ is selected from the group consisting of H and C₁₋₄-alkyl;

X is O, NR⁵ or CR⁵R^(5a);

R⁴ is selected from hydrogen or from the group consisting of C₁₋₄-alkyl,C₃₋₆-cycloalkyl, aryl, heterocycle and heteroaryl, each of which may beindependently substituted one or more times (or preferably between oneand five times) with a halogen atom or C₁₋₄-alkyl;

R⁵ is selected from hydrogen or oxo or the group consisting of hydroxyl,C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl-C₀₋₄-alkyl,aryl-C₀₋₄-alkyl, heterocycle-C₀₋₄-alkyl and heteroaryl-C₀₋₄-alkyl, eachof which may be independently substituted one or more times (orpreferably between one and five times) with a halogen atom, aryl,trihalomethyl, or C₁₋₄-alkyl;

R^(5a) is selected from the group consisting of hydrogen, hydroxyl,C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl-C₀₋₄-alkyl,aryl-C₀₋₄-alkyl and heteroaryl-C₀₋₄-alkyl,

or R⁴ and R⁵ may together form a fused dimethyl cyclopropyl ring, afused cyclopentane ring, a fused phenyl ring or a fused pyridyl ring,each of which may be substituted with a halogen atom, aryl,trihalomethyl, or C₁₋₄-alkyl;

or R⁵ and R^(5a) may together form a spirocarbocyclic saturated ringhaving between 3 and 6 carbon ring atoms which is optionally substitutedby 0-2 substituents selected from halogen, C₁₋₆-alkyl, C₂₋₆-alkenyl,C₂₋₆-alkynyl, C₁₋₆-alkoxy, C₃₋₇-cycloalkyl-C₀₋₄-alkyl,phenyl-C₀₋₄-alkyl, naphthyl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, or twosubstituents taken together form a fused or spirocyclic 3 to 7 memberedcarbocyclic ring, each of which is substituted with 0-3 independentlyselected halogen atoms or C₁₋₄-alkyl groups;

R⁸, R¹⁰ and R¹¹ are each, independently, selected from the groupconsisting of H and C₁₋₄-alkyl;

R⁶, R⁷ and R¹³ is H;

R⁹ and R¹² are each, independently, selected from the group consistingof hydrogen, C₁₋₄-alkyl and C₃₋₆-cycloalkyl; and

V is also selected from the group consisting of -Q¹-Q², wherein Q¹ isabsent, C(O), N(H), N(C₁₋₄-alkyl), C═N(CN), C═N(SO₂CH₃),C═N—COH—C₁₋₄-alkyl, or C═N—COH, and Q² is hydrogen or is selected fromthe group consisting of C₁₋₄-alkyl, O—C₁₋₄-alkyl, NH₂, N(H)—C₁₋₄-alkyl,N(C₁₋₄-alkyl)₂, SO₂-aryl, SO₂—C₁₋₄-alkyl, C₃₋₆-cycloalkyl-C₀₋₄-alkyl,aryl, heteroaryl and heterocycle, each of which may be independentlysubstituted one or more times with a halogen atom, C₁₋₄-alkyl,C₁₋₄-alkyl substituted by one or more halogen atoms, or C₃₋₆-cycloalkyl;

or R³ and W can together form a 6-membered ring of the formula II:

wherein formula II may be further substituted;

or when y is 0, R¹⁰ and V can form a cyclopropyl ring that may befurther substituted by an amide group.

In another embodiment of Formula I or Formula III, R¹⁴ is C(O).

In yet another embodiment of Formula I or Formula III, y is 0, and R¹⁰and V form a cyclopropyl ring that is substituted withC(O)N(H)-pyrazine.

In still another embodiment of Formula I, wherein R⁴, R⁶ and R⁷ arehydrogen, and R⁵ is aryl-C₀₋₃-alkyl, —O-heteroaryl, orheteroaryl-C₀₋₃-alkyl, wherein aryl and heteroaryl may be independentlysubstituted one or more times (or preferably between one and five times)with a halogen atom, aryl, trihalomethyl, C₃₋₆-cycloalkyl or C₁₋₄-alkyl.

In one embodiment of Formula I, n is 1, and R⁴ and R⁵ together form thefollowing fused ring systems:

wherein R¹⁸ is selected from the group consisting of hydrogen, a halogenatom, aryl, trihalomethyl, and C₁₋₄-alkyl.

In another embodiment of Formula I, R⁵ is selected from the groupconsisting of piperidine, phenyl, —O-pyridinyl and CH₂-pyridinyl,wherein the phenyl and pyridinyl groups may be independently substitutedone or more times (or preferably between one and five times) with ahalogen atom or C₁₋₄-alkyl.

In yet another embodiment of Formula I, R⁵ is 5-chloro-pyridin-2-yl.

In still another embodiment of Formula I, R⁵ is selected from the groupconsisting of

wherein R²¹ is independently selected from the group consisting ofC₁₋₄-alkyl and aryl.

Yet other compounds of Formula I or Formula III include those compoundsin which X is CR_(5a), R_(5a) is hydrogen or methyl, and R₅ is a residueselected from the group consisting of:

wherein R₈ is selected from hydrogen, methyl, ethyl, mono-, di-, ortri-fluoromethyl, mono-, di-, or tri-fluoromethoxy, fluoro, and chloro.

In still other compounds of Formula I or Formula III include thosecompounds in which the residue

is a residue of the formula:

wherein R₆ is hydrogen, methyl, ethyl, and mono-, di-, andtri-fluoromethyl; R₈ is selected from R₈ is selected from hydrogen,methyl, ethyl, mono-, di-, or tri-fluoromethyl, mono-, di-, ortri-fluoromethoxy, fluoro, and chloro.

Still other compounds of Formula I or Formula III include thosecompounds in which X is CR_(5a), R_(5a) is hydrogen or methyl, and R₅ isa residue selected from the group consisting of:

In still other embodiments, compounds of Formula I include thosecompounds in which CR⁵R^(5a), when taken in combination, form aspirocyclic 3 to 6 member carbocyclic ring. Certain spirocyclic ringsinclude groups of the formula:

whereinf is 0, 1, 2, 3, 4 or 5;R_(5b) and R₅ are independently selected from hydrogen halogen,C₁₋₆-alkyl, C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy,C₃₋₇-cycloalkyl-C₀₋₄-alkyl, phenyl-C₀₋₄-alkyl, naphthyl-C₀₋₄-alkyl,heteroaryl-C₀₋₄-alkyl, or two substituents taken together form a fusedor spirocyclic 3 to 7 membered carbocyclic ring, each of which issubstituted with 0-3 independently selected halogen atoms or C₁₋₄-alkylgroups.

In still other embodiments, compounds of Formula I include thosecompounds in which X is CR⁵R^(5a), R⁴ is hydrogen, and R⁵ and R^(5a)taken in combination form a 3 to 6 member spirocyclic carbocyclesubstituted with 0-2 substituents selected from halogen, C₁₋₆-alkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, C₁₋₆-alkoxy, C₃₋₇-cycloalkyl-C₀₋₄-alkyl,phenyl-C₀₋₄-alkyl, naphthyl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, or twosubstituents taken together form a fused or spirocyclic 3 to 7 memberedcarbocyclic ring, each of which is substituted with 0-3 independentlyselected halogen atoms or C₁₋₄-alkyl groups.

Certain compounds of Formula I include those compounds of the formula:

whereinm and n are 0 or 1 such that a sum of m and n equals 1 or 2;R_(a) is hydrogen, C₁₋₄alkyl, or phenyl;R_(b) is hydrogen, C₁₋₄alkyl, C₁₋₄alkoxy-C₀₋₄alkyl, mono- anddi-C₁₋₄alkylaminoC₀₋₄alkyl, mono- and di-C₁₋₄alkyl carboxamide,C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl, or phenylor R_(a) and R_(b) taken together form a fused or spirocyclic 3 to 6membered ring having 0, 1 or 2 ring heteroatoms selected from N, O andS, which fused or spirocyclic ring has 0 to 2 independently selectedsubstituents selected from halogen, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,and phenyl; andR_(c) represents 0 to 4 substituents which are independently selected ateach occurrence of R_(c) from the group consisting of halogen,C₁₋₄alkyl, and phenyl, or two geminal R_(c) substituents, taken incombination form a 3 to 6 member spirocyclic ring.

In certain other embodiments, compounds of Formula I include thosecompounds in which the divalent residue:

is selected from the group consisting of:

In certain other embodiments, compounds of Formula I include thosecompounds in which the divalent residue:

is selected from the group consisting of:

wherein R_(e) is absent, C(O), or S(O)₂; and R_(g) is selected hydrogenor selected from the group consisting of C₁₋₆alkyl, arylC₀₋₄alkyl,heteroarylC₀₋₄alkyl, heterocyclylC₀₋₄alkyl, and C₃₋₇cycloalkylC₀₋₄alkyl,each of which is substituted with 0 to 4 independently selectedsubstituents selected from the group consisting of cyano, halogen,hydroxyl, amino, thiol, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₁₋₈-alkoxy-C₀₋₄alkyl, C₁₋₈-haloalkyl, C₂₋₈-haloalkenyl,C₂₋₈-haloalkynyl, C₁₋₈-haloalkoxy, C₁₋₈-alkylthio, C₁₋₈-alkylsulfonyl,C₁₋₈-alkylsulfoxy, C₁₋₈-alkanoyl, C₁₋₈-alkoxycarbonyl,C₃₋₇-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl,COOH, C(O)NH₂, mono- and di-C₁₋₄-alkyl-carboxamide, mono- anddi-C₁₋₄-alkyl-amino-C₀₋₄alkyl, SO₃H, SO₂NH₂, and mono- anddi-C₁₋₄-alkylsulfonamide.

In certain embodiments, compounds of Formula III include those compoundsin which R⁵ and R^(5a), taken in combination, form a spirocyclic ringhaving between 3 and 7 ring atoms and having 0, 1, or 2 ringheteroatoms, which spirocyclic ring is substituted with a spirocyclic 3to 7 membered ring having 0, 1 or 2 ring heteroatoms selected from N, Oand S, and wherein each of the spirocyclic rings has 0 to 2independently selected substituents selected from cyano, halogen,hydroxyl, amino, thiol, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₁₋₈-alkoxy-C₀₋₄alkyl, C₁₋₈-haloalkyl, C₂₋₈-haloalkenyl,C₂₋₈-haloalkynyl, C₁₋₈-haloalkoxy, C₁₋₈-alkylthio, C₁₋₈-alkylsulfonyl,C₁₋₈-alkylsulfoxy, C₁₋₈-alkanoyl, C₁₋₈-alkoxycarbonyl,C₃₋₇-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl,COOH, C(O)NH₂, mono- and di-C₁₋₄-alkyl-carboxamide, mono- anddi-C₁₋₄-alkyl-amino-C₀₋₄alkyl, SO₃H, SO₂NH₂, and mono- anddi-C₁₋₄-alkylsulfonamide.

In another embodiment, compounds of Formula III include compounds of theformula:

whereink₁ and k₂ are 0 or 1 such that a sum of k₁ and k₂ equals 1 or 2;R_(a) and R_(b) taken together form a spirocyclic 3 to 6 membered ringhaving 0, 1 or 2 ring heteroatoms selected from N, O and S, which fusedor spirocyclic ring has 0 to 2 independently selected substituentsselected from halogen, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, and phenyl;R_(c) represents 0 to 2 substituents which are independently selected ateach occurrence of R_(c) from the group consisting of halogen,C₁₋₄alkyl, and phenyl, or two geminal R_(c) substituents, taken incombination form a 3 to 6 member spirocyclic ring;R₄ represents 0, 1, or 2 substituents each of which is independentlyselected from H and C₁₋₄-alkyl; andR₆ is hydrogen or C₁₋₄alkyl.

In still another aspect, compounds of Formula III include thosecompounds in which the divalent residue:

is selected from the group consisting of:

In yet other embodiments, compounds having the structure of Formula I orFormula III have substituents at R ⁶, R⁹, R¹¹, and R¹² which are each,independently, selected from the group consisting of:

wherein R³¹ is hydroxy or C₁₋₆alkoxy; andR³² is hydrogen, acetyl, C(O)O^(t)Bu, or C(O)N(H)^(t)Bu.

In certain other embodiments, compounds having the structure of FormulaI or Formula III, are substituted at R³ with a substituent selected fromthe group consisting of:

In one embodiment of Formula I or Formula III, W is selected from thegroup consisting of C(O)—C(O)NH₂, C(O)—C(O)N(H)-cyclopropyl,C(O)-benzothiazole, C(O)-benzoimidazole, C(O)-oxazole, C(O)-imidazole,and C(O)-oxadiazole, wherein the benzothiazole, benzoimidazole, oxazoleand oxadiazole groups may be independently substituted one or more times(or preferably between one and five times) with a halogen atom, aryl,trihalomethyl, C₃₋₆-cycloalkyl or C₁₋₄-alkyl.

In another embodiment of Formula I or Formula III, W is selected fromthe group consisting of

wherein R¹⁹ is selected from the group consisting of hydrogen, aryl,trihalomethyl, and C₁₋₄-alkyl.

In yet another embodiment of Formula I or Formula III, R² is selectedfrom the group consisting of propyl and (CH₂)₂-cyclobutyl.

In still another embodiment of Formula I or Formula III, R^(H) is H andR¹² is C₃₋₆-cycloalkyl.

In one embodiment of Formula I or Formula III, R¹² is cyclohexyl.

In another embodiment of Formula I or Formula III, V is selected fromthe group consisting of C(O)—N(H)-t-butyl.

In yet another embodiment of Formula I or Formula III, V is C(O)—R²⁰,wherein R²⁰ is selected from the group consisting of C₃₋₆-cycloalkyl,phenyl, pyrazine, benzoxazole, 4,4-dimethyl-4,5-dihydro-oxazole,benzoimidazole, pyrimidine, benzothiazole 1,1-dioxide and quinazoline,each of which may be further independently substituted with a halogenatom, CF₃, C₁₋₄-alkyl or C₃₋₆-cycloalkyl.

In still another embodiment of Formula I or Formula III, V is R²⁰ orC(O)—R²⁰, wherein R²⁰ is selected from the group consisting of

wherein b is 0, 1, or 2; and R₁₈ is selected from the group consistingof hydrogen, a halogen atom, aryl, trihalomethyl, and C₁₋₄-alkyl.

In another embodiment of Formula I or Formula III, V is selected fromthe group consisting of C₃₋₆-cycloalkyl, phenyl, pyrazine, benzooxazole,4,4-dimethyl-4,5-dihydro-oxazole, benzoimidazole, pyrimidine,benzothiazole 1,1-dioxide and quinazoline, each of which may be furtherindependently substituted with a halogen atom, CF₃, C₁₋₄-alkyl orC₃₋₆-cycloalkyl.

In certain embodiments, compounds of Formula I or Formula III comprise aV group selected from residues having the formula —C(O)—R²⁰, wherein R²⁰is a residue of the formula (i):

wherein R⁴⁴ is selected from the group consisting of: tent-butyl,isopropyl, cyclohexyl, spirocyclohexyl

and 1-methylcyclohexyl;and R⁷⁷ is selected from the group consisting of:

Where R⁷⁸ is selected from methyl, ethyl, isopropyl, tert-butyl andphenyl.

In yet other embodiments, compounds of Formula I or Formula III comprisea V group selected from residues having the formula —C(O)-V′, wherein V′is a residue of the formula (ii):

wherein R⁷⁹ is selected form the group consisting of methyl, ethyl,isopropyl, tert-butyl, sec-butyl, 4-methyl-butyl, 1,1-dimethylpropyl,1,1-dimethylbutyl, phenyl, benzyl, cyclopentyl, cyclohexyl, furylmethyl,and pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl).

In certain other embodiments, compounds of Formula I or Formula IIIcomprise a V group selected from residues having the formula —C(O)-V′,wherein V′ is a residue of the formula (iii):

wherein R⁷⁸ represents 0-3 groups independently selected from C₁₋₆alkyland C₃₋₆cycloalkyl.

In certain embodiments, compounds of Formula I or Formula III comprise aV group selected from residues having the formula —C(O)-V′, wherein V′is a residue of the formula (iv):

(iv)

wherein m is 1 or 2; n is 0, 1, 2, or 3;

R^(u), R^(v), and R^(w), are independently selected at each occurrencefrom the group consisting of hydrogen, C₁₋₆alkyl, arylC₀₋₄alkyl,heteroarylC₀₋₄alkyl, heterocyclylC₀₋₄alkyl, and cycloalkylC₀₋₄alkyl; or

R^(v) and R^(w), taken in combination, form a ring having between 3 and7 ring atoms and having 0, 1, 2 ring heteroatoms which is substitutedwith 0-2 alkyl groups and 0-1 spirocyclic groups.

R^(x) and R^(y) are each independently selected from the groupconsisting of phenyl, C₁₋₆alkyl, and C₃₋₆cycloalkyl, or R^(x) and R^(y)are each independently selected from the group consisting of phenyl,cyclopropyl, isopropyl, tert-butyl, and cyclohexyl.

In certain embodiments, compounds of Formula I or Formula III comprise aV group selected from residues having the formula —C(O)-V′, wherein V′is a residue selected from the group consisting of tert-butoxy,2,2-dimethylpropoxy, sec-butoxy, 1,2-dimethylpropoxy, 3-pentoxy,isopropoxy, C₁₋₉alkoxy, 2,2,2-trichloroethoxy,

wherein

Y¹¹ is selected from the group consisting of hydrogen, —C(O)OH,—C(O)OEt, —OMe, -Ph, —OPh, —NHMe, —NHAc, —NHPh, —CH(Me)₂, 1-triazolyl,1-imidazolyl, and —NHCH₂COOH;

Y¹² is selected from the group consisting of hydrogen, —C(O)OH,—C(O)OMe, —OMe, F, Cl, and Br;

Y¹³ is selected from the group consisting of the following moieties:

Y¹⁴ is S(O)₂Me, —C(O)Me, -Boc, -iBoc, Cbz, or -Alloc;

Y¹⁵ and Y¹⁶ can be the same or different and are independently selectedfrom the group consisting of alkyl, aryl, heteroalkyl, and heteroaryl;

Y¹⁷ is —CF₃, —NO₂, —C(O)NH₂, —OH, —C(O)OCH₃, —OCH₃, —OC₆H₅, —C₆H₅,—C(O)C₆H₅, —NH₂, or —C(O)OH; and

Y¹⁸ is —C(O)OCH₃, —NO₂, —N(CH₃)₂, F, —OCH₃, —C(H)₂C(O)OH, —C(O)OH,—S(O)₂NH₂, or —N(H)C(O)CH₃

In one embodiment, any of the C₃₋₆-cycloalkyl groups may beindependently substituted one or more times (or preferably between oneand five times) with a halogen atom, aryl, trihalomethyl, or C₁₋₄-alkyl.

In another embodiment of formula I, R⁴ is H and R⁵ is aryl-C₀₋₃-alkyl,—O-heterocycle, or heterocycle-C₀₋₃-alkyl, wherein aryl and heterocyclemay be independently substituted one or more times (or preferablybetween one and five times) with a halogen atom, aryl, trihalomethyl,C₃₋₆-cycloalkyl or C₁₋₄-alkyl.

In yet another embodiment of Formula I or Formula III, W is selectedfrom the group consisting of C(O)—C(O)N(R²³)₂, wherein R²³ isindependently selected from hydrogen or from the group consisting ofC₁₋₄-alkyl, C₃₋₆-cycloalkylC₀₋₄alkyl, aryl and heterocycle, each ofwhich may be independently substituted one or more times (or preferablybetween one and five times) with a halogen atom or C₁₋₄-alkyl.

In still another embodiment of Formula I or Formula III, W isC(O)—C(O)-cyclopropyl

In one embodiment of Formula I or Formula III, any of the heterocyclegroups are independently selected from the group consisting ofacridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrazolyl, indolyl,benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl,quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl,pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline,benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl,benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl,cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl,indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline,isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrahydropyranyl, tetrazolyl,tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl,azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl,pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof, each of which may be independently further substitutedone or more times (or preferably between one and five times) with ahalogen atom, C₁₋₄-alkyl, C₁₋₄-alkyl substituted by one or more halogenatoms, or C₃₋₆-cycloalkyl.

Preferred embodiments of the compounds of the invention (includingpharmaceutically acceptable salts thereof, as well as enantiomers,stereoisomers, rotamers, tautomers, diastereomers, or racemates thereof)are shown below in Table A and Table B, and are also considered to be“compounds of the invention.”

TABLE A Compound Structure No.

A-1 

A-2 

A-3 

A-4 

A-5 

A-6 

A-7 

A-8 

A-9 

A-10 

A-11 

A-12 

A-13 

A-14 

A-15 

A-16 

A-17 

A-18 

A-19 

A-20 

A-21 

A-22 

A-23 

A-24 

A-25 

A-26 

A-27 

A-28 

A-29 

A-30 

A-31 

A-32 

A-33 

A-34 

A-35 

A-36 

A-37 

A-38 

A-39 

A-40 

A-41 

A-42 

A-43 

A-44 

A-45 

A-46 

A-47 

A-48 

A-49 

A-50 

A-51 

A-52 

A-53 

A-54 

A-55 

A-56 

A-57 

A-58 

A-59 

A-60 

A-61 

A-62 

A-63 

A-64 

A-65 

A-66 

A-67 

A-68 

A-69 

A-70 

A-71 

A-72 

A-73 

A-74 

A-75 

A-76 

A-77 

A-78 

A-79 

A-80 

A-81 

A-82 

A-83 

A-84 

A-85 

A-86 

A-87 

A-88 

A-89 

A-90 

A-91 

A-92 

A-93 

A-94 

A-95 

A-96 

A-97 

A-98 

A-99 

A-100

A-101

A-102

A-103

A-104

A-105

A-106

A-107

A-108

A-109

A-110

A-111

A-112

A-113

A-114

A-115

A-116

A-117

A-118

A-119

A-120

A-121

A-122

A-123

A-124

A-125

A-126

A-127

A-128

A-129

A-130

A-131

A-132

A-133

A-134

A-135

A-136

A-137

A-138

A-139

A-140

A-141

A-142

A-143

A-144

A-145

A-146

A-147

A-148

A-149

A-150

A-151

TABLE B Compound Structure No.

B-1

B-2

B-3

B-4

B-5

B-6

B-7

B-8

B-9

B-10

B-11

B-12

B-13

B-14

B-15

B-16

B-17

B-18

B-19

B-20

B-21

B-22

B-23

B-24

B-25

B-26

B-27

B-28

B-29

B-30

B-31

B-32

B-33

B-34

B-35

B-36

B-37

B-38

B-39

B-40

B-41

B-42

B-43

B-44

B-45

B-46

B-47

B-48

B-49

B-50

B-51

B-52

B-53

B-54

B-55

B-56

B-57

B-58

B-59

B-60

B-61

B-62

B-63

B-64

B-65

B-66

B-67

B-68

B-69

B-70

B-71

B-72

B-73

B-74

B-75

B-76

B-77

B-78

B-79

B-80

B-81

B-82

B-83

B-84

B-85

B-86

B-87

B-88

B-89

B-90

B-91

B-92

B-93

B-94

B-95

B-96

B-97

B-98

B-99

B-100

B-101

B-102

B-103

B-104

B-105

B-106

B-107

B-108

B-109

B-110

B-111

B-112

B-113

B-114

B-115

B-116

B-117

B-118

B-119

B-120

B-121

B-122

B-123

B-124

B-125

B-126

B-127

B-128

B-129

B-130

B-131

B-132

B-133

B-134

B-135

B-136

B-137

B-138

B-139

B-140

B-141

B-142

B-143

B-144

B-145

B-146

B-147

B-148

B-149

B-150

B-151

B-152

B-153

B-154

B-155

B-156

B-157

B-158

B-159

B-160

B-161

B-162

B-163

B-164

B-165

B-166

B-167

B-168

B-169

B-170

B-171

B-172

B-173

B-174

B-175

B-176

B-177

B-178

B-179

B-180

B-181

B-182

B-183

B-184

B-185

B-186

B-187

B-188

B-189

B-190

B-191

B-192

B-193

B-194

B-195

B-196

B-197

B-198

B-199

B-200

B-201

B-202

B-203

B-204

B-205

B-206

B-207

B-208

B-209

B-210

B-211

B-212

B-213

B-214

B-215

B-216

B-217

B-218

B-219

B-220

B-221

B-222

B-223

B-224

B-225

B-226

B-227

B-228

B-229

B-230

B-231

B-232

B-233

B-234

B-235

B-236

B-237

B-238

B-239

B-240

B-241

B-242

B-243

B-244

B-245

B-246

B-247

B-248

B-249

B-250

B-251

B-252

B-253

B-254

B-255

B-256

B-257

B-258

B-259

B-260

B-261

B-262

B-263

B-264

B-265

B-266

B-267

B-268

B-269

B-270

B-271

B-272

B-273

B-274

B-275

B-276

B-277

B-278

B-279

B-280

B-281

B-282

B-283

B-284

B-285

B-286

B-287

B-288

B-289

B-290

B-291

B-292

B-293

B-294

B-295

B-296

B-297

B-298

B-299

B-300

B-301

B-302

B-303

B-304

B-305

B-306

B-307

B-308

B-309

B-310

B-311

B-312

Using the HCV NS3-4A protease and Luciferase-HCV replicon assaysdescribed in the exemplification section below, the compounds of theinvention (including compounds of Table A depicted above) are found toshow IC₅₀ values for HCV inhibition in the range from 10 to more than100 μM, or 0.5 to 30 μM, including, for example, the range from 0.5 to10 μM or less.

In certain embodiments, a compound of the present invention is furthercharacterized as a modulator of HCV, including a mammalian HCV, andespecially including a human HCV. In a preferred embodiment, thecompound of the invention is an HCV inhibitor.

In certain embodiments, the compound of the invention is not VX-950 orSch 503034 (see, e.g., Curr. Med. Chem., 2005, 12, 2317-2342; andAntimicrob Agents Chemother. 2006 March; 50(3):1013-20, both of whichare incorporated herein by reference in their entirety).

In other embodiments, the compounds of the invention are not the speciesdescribed in International Patent Application Nos. WO 2005/058821,WO/2005/021584, WO/01/18369, WO/03/062265, WO/02/18369, WO/2003/087092and U.S. Pat. App. No. 2002/0032175.

The terms “HCV-associated state” or “HCV-associated disorder” includedisorders and states (e.g., a disease state) that are associated withthe activity of HCV, e.g., infection of HCV in a subject. HCV-associatedstates include HCV-infection, liver cirrhosis, chronic liver disease,hepatocellular carcinoma, cryoglobulinaemia, non-Hodgkin's lymphoma, anda suppressed innate intracellular immune response.

HCV-associated states are often associated with the NS3 serine proteaseof HCV, which is responsible for several steps in the processing of theHCV polyprotein into smaller functional proteins. NS3 protease forms aheterodimeric complex with the NS4A protein, an essential cofactor thatenhances enzymatic activity, and is believed to help anchor HCV to theendoplasmic reticulum. NS3 first autocatalyzes hydrolysis of theNS3-NS4A juncture, and then cleaves the HCV polyprotein intermolecularlyat the NS4A-NS4B, NS4B-NS5A and NS5A-NS5B intersections. This process isassociated with replication of HCV in a subject. Inhibiting ormodulating the activity of one or more of the NS3, NS4A, NS4B, NS5A andNS5B proteins will inhibit or modulate replication of HCV in a subject,thereby preventing or treating the HCV-associated state. In a particularembodiment, the HCV-associated state is associated with the activity ofthe NS3 protease. In another particular embodiment, the HCV-associatedstate is associated with the activity of NS3-NS4A heterodimeric complex.

In one embodiment, the compounds of the invention are NS3/NS4A proteaseinhibitors. In another embodiment, the compounds of the invention areNS2/NS3 protease inhibitors.

Without being bound by theory, it is believed that the disruption of theabove protein-protein interactions by the compounds of the inventionwill interfere with viral polyprotein processing by the NS3 protease andthus viral replication.

HCV-associated disorders also include HCV-dependent diseases.HCV-dependent diseases include, e.g., any disease or disorder thatdepend on or related to activity or misregulation of at least one strainof HCV.

The present invention includes treatment of HCV-associated disorders asdescribed above, but the invention is not intended to be limited to themanner by which the compound performs its intended function of treatmentof a disease. The present invention includes treatment of diseasesdescribed herein in any manner that allows treatment to occur, e.g., HCVinfection.

In a related embodiment, the compounds of the invention can be usefulfor treating diseases related to HIV, as well as HIV infection and AIDS(Acquired Immune Deficiency Syndrome).

In certain embodiments, the invention provides a pharmaceuticalcomposition of any of the compounds of the present invention. In arelated embodiment, the invention provides a pharmaceutical compositionof any of the compounds of the present invention and a pharmaceuticallyacceptable carrier or excipient of any of these compounds. In certainembodiments, the invention includes the compounds as novel chemicalentities.

In one embodiment, the invention includes a packaged HCV-associateddisorder treatment. The packaged treatment includes a compound of theinvention packaged with instructions for using an effective amount ofthe compound of the invention for an intended use.

The compounds of the present invention are suitable as active agents inpharmaceutical compositions that are efficacious particularly fortreating HCV-associated disorders. The pharmaceutical composition invarious embodiments has a pharmaceutically effective amount of thepresent active agent along with other pharmaceutically acceptableexcipients, carriers, fillers, diluents and the like. The phrase,“pharmaceutically effective amount” as used herein indicates an amountnecessary to administer to a host, or to a cell, issue, or organ of ahost, to achieve a therapeutic result, especially an anti-HCV effect,e.g., inhibition of proliferation of the HCV virus, or of any otherHCV-associated disease.

In one embodiment, the diseases to be treated by compounds of theinvention include, for example, HCV infection, liver cirrhosis, chronicliver disease, hepatocellular carcinoma, cryoglobulinaemia,non-Hodgkin's lymphoma, and a suppressed innate intracellular immuneresponse.

In other embodiments, the present invention provides a method forinhibiting the activity of HCV. The method includes contacting a cellwith any of the compounds of the present invention. In a relatedembodiment, the method further provides that the compound is present inan amount effective to selectively inhibit the activity of one or moreof the NS3, NS4A, NS4B, NS5A and NS5B proteins. In another relatedembodiment, the method provides that the compound is present in anamount effective to diminish the HCV RNA load in a subject.

In other embodiments, the present invention provides a use of any of thecompounds of the invention for manufacture of a medicament to treat HCVinfection in a subject.

In other embodiments, the invention provides a method of manufacture ofa medicament, including formulating any of the compounds of the presentinvention for treatment of a subject.

DEFINITIONS

The term “treat,” “treated,” “treating” or “treatment” includes thediminishment or alleviation of at least one symptom associated or causedby the state, disorder or disease being treated. In certain embodiments,the treatment comprises the induction of an HCV-inhibited state,followed by the activation of the HCV-modulating compound, which wouldin turn diminish or alleviate at least one symptom associated or causedby the HCV-associated state, disorder or disease being treated. Forexample, treatment can be diminishment of one or several symptoms of adisorder or complete eradication of a disorder.

The term “subject” is intended to include organisms, e.g., prokaryotesand eukaryotes, which are capable of suffering from or afflicted with anHCV-associated disorder. Examples of subjects include mammals, e.g.,humans, dogs, cows, horses, pigs, sheep, goats, cats, mice, rabbits,rats, and transgenic non-human animals. In certain embodiments, thesubject is a human, e.g., a human suffering from, at risk of sufferingfrom, or potentially capable of suffering from an HCV-associateddisorder, and for diseases or conditions described herein, e.g., HCVinfection. In another embodiment, the subject is a cell.

The language “HCV-modulating compound,” “modulator of HCV” or “HCVinhibitor” refers to compounds that modulate, e.g., inhibit, orotherwise alter, the activity of HCV. Similarly, an “NS3/NS4A proteaseinhibitor,” or an “NS2/NS3 protease inhibitor” refers to a compound thatmodulates, e.g., inhibits, or otherwise alters, the interaction of theseproteases with one another. Examples of HCV-modulating compounds includecompounds of Formula I or Formula III, as well as Table A and Table B(including pharmaceutically acceptable salts thereof, as well asenantiomers, stereoisomers, rotamers, tautomers, diastereomers, orracemates thereof).

Additionally, the method includes administering to a subject aneffective amount of an HCV-modulating compound of the invention, e.g.,HCV-modulating compounds of Formula I or Formula III, as well as Table Aand Table B (including pharmaceutically acceptable salts thereof, aswell as enantiomers, stereoisomers, rotamers, tautomers, diastereomers,or racemates thereof).

The term “alkyl” includes saturated aliphatic groups, includingstraight-chain alkyl groups (e.g., methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl, decyl, etc.), branched-chain alkyl groups(isopropyl, tert-butyl, isobutyl, etc.), cycloalkyl (alicyclic) groups(cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl), alkylsubstituted cycloalkyl groups, and cycloalkyl substituted alkyl groups.Furthermore, the expression “C_(x)-C_(y)-alkyl”, wherein x is 1-5 and yis 2-10 indicates a particular alkyl group (straight- or branched-chain)of a particular range of carbons. For example, the expressionC₁-C₄-alkyl includes, but is not limited to, methyl, ethyl, propyl,butyl, isopropyl, tert-butyl, isobutyl and sec-butyl. Moreover, the termC₃₋₆-cycloalkyl includes, but is not limited to, cyclopropyl,cyclopentyl, and cyclohexyl. As discussed below, these alkyl groups, aswell as cycloalkyl groups, may be further substituted. “C₀-C_(n)alkyl”refers to a single covalent bond (C₀) or an alkyl group having from 1 ton carbon atoms; for example “C₀-C₄alkyl” refers to a single covalentbond or a C₁-C₄alkyl group; “C₀-C₈alkyl” refers to a single covalentbond or a C₁-C₈alkyl group. In some instances, a substituent of an alkylgroup is specifically indicated. For example, “C₁-C₄hydroxyalkyl” refersto a C₁-C₄alkyl group that has at least one hydroxy substituent.

“Alkylene” refers to a divalent alkyl group, as defined above.C₀-C₄alkylene is a single covalent bond or an alkylene group having from1 to 4 carbon atoms; and C₀-C₆alkylene is a single covalent bond or analkylene group having from 1 to 6 carbon atoms.

A “cycloalkyl” is a group that comprises one or more saturated and/orpartially saturated rings in which all ring members are carbon, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, adamantyl, decahydro-naphthalenyl, octahydro-indenyl, andpartially saturated variants of the foregoing, such as cyclohexenyl.Cycloalkyl groups do not comprise an aromatic ring or a heterocyclicring. Certain cycloalkyl groups are C₃-C₈cycloalkyl, in which the groupcontains a single ring with from 3 to 8 ring members. A“(C₃-C₈cycloalkyl)C₀-C₄alkyl” is a C₃-C₈cycloalkyl group linked via asingle covalent bond or a C₁-C₄alkylene group.

Moreover, alkyl (e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl,etc.) include both “unsubstituted alkyl” and “substituted alkyl”, thelatter of which refers to alkyl moieties having substituents replacing ahydrogen on one or more carbons of the hydrocarbon backbone, which allowthe molecule to perform its intended function.

The term “substituted” is intended to describe moieties havingsubstituents replacing a hydrogen on one or more atoms, e.g. C, O or N,of a molecule. Such substituents can include, for example, alkenyl,alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates,alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, morpholino,phenol, benzyl, phenyl, piperazine, cyclopentane, cyclohexane, pyridine,5H-tetrazole, triazole, piperidine, or an aromatic or heteroaromaticmoiety.

Further examples of substituents of the invention, which are notintended to be limiting, include moieties selected from straight orbranched alkyl (preferably C₁-C₅), cycloalkyl (preferably C₃-C₈), alkoxy(preferably C₁-C₆), thioalkyl (preferably C₁-C₆), alkenyl (preferablyC₂-C₆), alkynyl (preferably C₂-C₆), heterocyclic, carbocyclic, aryl(e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl),aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl,heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group,heteroarylcarbonyl, or heteroaryl group, (CR′R″)₀₋₃NR′R″ (e.g., —NH₂),(CR′R″)₀₋₃CN (e.g., —CN), —NO₂, halogen (e.g., —F, —Cl, —Br, or —I),(CR′R″)₀₋₃C(halogen)₃ (e.g., —CF₃), (CR′R″)₀₋₃CH(halogen)₂,(CR′R″)₀₋₃CH₂(halogen), (CR′R″)₀₋₃CONR′R″, (CR′R″)₀₋₃(CNH)NR′R″,(CR′R″)₀₋₃S(O)₁₋₂NR′R″, (CR′R″)₀₋₃CHO, (CR′R″)₀₋₃O(CR′R″)₀₋₃H,(CR′R″)₀₋₃S(O)₀₋₃R′ (e.g., —SO₃H, —OSO₃H), (CR′R″)₀₋₃O(CR′R″)₀₋₃H (e.g.,—CH₂OCH₃ and —OCH₃), (CR′R″)₀₋₃S(CR′R″)₀₋₃H (e.g., —SH and —SCH₃),(CR′R″)₀₋₃OH (e.g., —OH), (CR′R″)₀₋₃COR′, (CR′R″)₀₋₃ (substituted orunsubstituted phenyl), (CR′R″)₀₋₃(C₃-C₁₈ cycloalkyl), (CR′R″)₀₋₃CO₂R′(e.g., —CO₂H), or (CR′R″)₀₋₃OR′ group, or the side chain of anynaturally occurring amino acid; wherein R′ and R″ are each independentlyhydrogen, a C₁-C₅ alkyl, C₂-C₅ alkenyl, C₂-C₅ alkynyl, or aryl group.Such substituents can include, for example, halogen, hydroxyl,alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl,aminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato,phosphinato, cyano, amino (including alkyl amino, dialkylamino,arylamino, diarylamino, and alkylarylamino), acylamino (includingalkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino,imino, oxime, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl,cyano, azido, heterocyclyl, or an aromatic or heteroaromatic moiety. Incertain embodiments, a carbonyl moiety (C═O) may be further derivatizedwith an oxime moiety, e.g., an aldehyde moiety may be derivatized as itsoxime (—C═N—OH) analog. It will be understood by those skilled in theart that the moieties substituted on the hydrocarbon chain canthemselves be substituted, if appropriate. Cycloalkyls can be furthersubstituted, e.g., with the substituents described above. An “aralkyl”moiety is an alkyl substituted with an aryl (e.g., phenylmethyl (i.e.,benzyl)).

The term “alkenyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one double bond.

For example, the term “alkenyl” includes straight-chain alkenyl groups(e.g., ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl, etc.), branched-chain alkenyl groups, cycloalkenyl(alicyclic) groups (cyclopropenyl, cyclopentenyl, cyclohexenyl,cycloheptenyl, cyclooctenyl), alkyl or alkenyl substituted cycloalkenylgroups, and cycloalkyl or cycloalkenyl substituted alkenyl groups. Theterm alkenyl further includes alkenyl groups that include oxygen,nitrogen, sulfur or phosphorous atoms replacing one or more carbons ofthe hydrocarbon backbone. In certain embodiments, a straight chain orbranched chain alkenyl group has 6 or fewer carbon atoms in its backbone(e.g., C₂-C₆ for straight chain, C₃-C₆ for branched chain). Likewise,cycloalkenyl groups may have from 3-8 carbon atoms in their ringstructure, and more preferably have 5 or 6 carbons in the ringstructure. The term C₂-C₆ includes alkenyl groups containing 2 to 6carbon atoms.

Moreover, the term alkenyl includes both “unsubstituted alkenyls” and“substituted alkenyls”, the latter of which refers to alkenyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “alkynyl” includes unsaturated aliphatic groups analogous inlength and possible substitution to the alkyls described above, butwhich contain at least one triple bond.

For example, the term “alkynyl” includes straight-chain alkynyl groups(e.g., ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl,nonynyl, decynyl, etc.), branched-chain alkynyl groups, and cycloalkylor cycloalkenyl substituted alkynyl groups. The term alkynyl furtherincludes alkynyl groups that include oxygen, nitrogen, sulfur orphosphorous atoms replacing one or more carbons of the hydrocarbonbackbone. In certain embodiments, a straight chain or branched chainalkynyl group has 6 or fewer carbon atoms in its backbone (e.g., C₂-C₆for straight chain, C₃-C₆ for branched chain). The term C₂-C₆ includesalkynyl groups containing 2 to 6 carbon atoms.

Moreover, the term alkynyl includes both “unsubstituted alkynyls” and“substituted alkynyls”, the latter of which refers to alkynyl moietieshaving substituents replacing a hydrogen on one or more carbons of thehydrocarbon backbone. Such substituents can include, for example, alkylgroups, alkynyl groups, halogens, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl,phosphate, phosphonato, phosphinato, cyano, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “amine” or “amino” should be understood as being broadlyapplied to both a molecule, or a moiety or functional group, asgenerally understood in the art, and may be primary, secondary, ortertiary. The term “amine” or “amino” includes compounds where anitrogen atom is covalently bonded to at least one carbon, hydrogen orheteroatom. The terms include, for example, but are not limited to,“alkylamino,” “arylamino,” “diarylamino,” “alkylarylamino,”“alkylaminoaryl,” “arylaminoalkyl,” “alkaminoalkyl,” “amide,” “amido,”and “aminocarbonyl.” The term “alkyl amino” comprises groups andcompounds wherein the nitrogen is bound to at least one additional alkylgroup. The term “dialkyl amino” includes groups wherein the nitrogenatom is bound to at least two additional alkyl groups. The term“arylamino” and “diarylamino” include groups wherein the nitrogen isbound to at least one or two aryl groups, respectively. The term“alkylarylamino,” “alkylaminoaryl” or “arylaminoalkyl” refers to anamino group which is bound to at least one alkyl group and at least onearyl group. The term “alkaminoalkyl” refers to an alkyl, alkenyl, oralkynyl group bound to a nitrogen atom which is also bound to an alkylgroup.

The term “amide,” “amido” or “aminocarbonyl” includes compounds ormoieties which contain a nitrogen atom which is bound to the carbon of acarbonyl or a thiocarbonyl group. The term includes “alkaminocarbonyl”or “alkylaminocarbonyl” groups which include alkyl, alkenyl, aryl oralkynyl groups bound to an amino group bound to a carbonyl group. Itincludes arylaminocarbonyl and arylcarbonylamino groups which includearyl or heteroaryl moieties bound to an amino group which is bound tothe carbon of a carbonyl or thiocarbonyl group. The terms“alkylaminocarbonyl,” “alkenylaminocarbonyl,” “alkynylaminocarbonyl,”“arylaminocarbonyl,” “alkylcarbonylamino,” “alkenylcarbonylamino,”“alkynylcarbonylamino,” and “arylcarbonylamino” are included in term“amide.” Amides also include urea groups (aminocarbonylamino) andcarbamates (oxycarbonylamino).

The term “aryl” includes groups, including 5- and 6-membered single-ringaromatic groups that may include from zero to four heteroatoms, forexample, phenyl, pyrrole, furan, thiophene, thiazole, isothiaozole,imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine,pyrazine, pyridazine, and pyrimidine, and the like. Furthermore, theterm “aryl” includes multicyclic aryl groups, e.g., tricyclic, bicyclic,e.g., naphthalene, benzoxazole, benzodioxazole, benzothiazole,benzoimidazole, benzothiophene, methylenedioxyphenyl, quinoline,isoquinoline, anthryl, phenanthryl, napthridine, indole, benzofuran,purine, benzofuran, deazapurine, or indolizine. Those aryl groups havingheteroatoms in the ring structure may also be referred to as “arylheterocycles”, “heterocycles,” “heteroaryls” or “heteroaromatics.” Thearomatic ring can be substituted at one or more ring positions with suchsubstituents as described above, as for example, alkyl, halogen,hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl,alkylthiocarbonyl, phosphate, phosphonato, phosphinato, cyano, amino(including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Arylgroups can also be fused or bridged with alicyclic or heterocyclic ringswhich are not aromatic so as to form a polycycle (e.g., tetralin).

Certain aryl groups recited herein are C₆-C₁₀arylC₀-C₈alkyl groups(i.e., groups in which a 6- to 10-membered carbocyclic group comprisingat least one aromatic ring is linked via a single covalent bond or aC₁-C₈alkylene group). Such groups include, for example, phenyl andindanyl, as well as groups in which either of the foregoing is linkedvia C₁-C₈alkylene, preferably via C₁-C₄alkylene. Phenyl groups linkedvia a single covalent bond or C₁-C₆alkylene group are designatedphenylC₀-C₆alkyl (e.g., benzyl, 1-phenyl-ethyl, 1-phenyl-propyl and2-phenyl-ethyl).

The term heteroaryl, as used herein, represents a stable monocyclic orbicyclic ring of up to 7 atoms in each ring, wherein at least one ringis aromatic and contains from 1 to 4 heteroatoms selected from the groupconsisting of O, N and S. Heteroaryl groups within the scope of thisdefinition include but are not limited to: acridinyl, carbazolyl,cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl,thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl,oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl,pyrimidinyl, pyrrolyl, tetrahydroquinoline. As with the definition ofheterocycle below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic orcontains no heteroatoms, it is understood that attachment is via thearomatic ring or via the heteroatom containing ring, respectively.

The term “heterocycle” or “heterocyclyl” as used herein is intended tomean a 5- to 10-membered aromatic or nonaromatic heterocycle containingfrom 1 to 4 heteroatoms selected from the group consisting of O, N andS, and includes bicyclic groups. “Heterocyclyl” therefore includes theabove mentioned heteroaryls, as well as dihydro and tetrathydro analogsthereof. Further examples of “heterocyclyl” include, but are not limitedto the following: benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,thiazolyl, thienyl, triazolyl, azetidinyl, 1,4-dioxanyl,hexahydroazepinyl, piperazinyl, piperidinyl, pyridin-2-onyl,pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl,dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzoxazolyl,dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroisooxazolyl,dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl,dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. Attachment of a heterocyclyl substituent can occur viaa carbon atom or via a heteroatom.

A “heterocycleC₀-C₈alkyl” is a heterocyclic group linked via a singlecovalent bond or C₁-C₈alkylene group. A (4- to 7-memberedheterocycle)C₀-C₈alkyl is a heterocyclic group (e.g., monocyclic orbicyclic) having from 4 to 7 ring members linked via a single covalentbond or an alkylene group having from 1 to 8 carbon atoms. A“(6-membered heteroaryl)C₀-C₆alkyl” refers to a heteroaryl group linkedvia a direct bond or C₁-C₆alkyl group.

The term “acyl” includes compounds and moieties which contain the acylradical (CH₃CO—) or a carbonyl group. The term “substituted acyl”includes acyl groups where one or more of the hydrogen atoms arereplaced by for example, alkyl groups, alkynyl groups, halogens,hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano,amino (including alkyl amino, dialkylamino, arylamino, diarylamino, andalkylarylamino), acylamino (including alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl,alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl,sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido,heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

The term “acylamino” includes moieties wherein an acyl moiety is bondedto an amino group. For example, the term includes alkylcarbonylamino,arylcarbonylamino, carbamoyl and ureido groups.

The term “alkoxy” includes substituted and unsubstituted alkyl, alkenyl,and alkynyl groups covalently linked to an oxygen atom. Examples ofalkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy,and pentoxy groups and may include cyclic groups such as cyclopentoxy.Examples of substituted alkoxy groups include halogenated alkoxy groups.The alkoxy groups can be substituted with groups such as alkenyl,alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl,arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate,phosphonato, phosphinato, cyano, amino (including alkyl amino,dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino(including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido),amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate,sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro,trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromaticor heteroaromatic moieties. Examples of halogen substituted alkoxygroups include, but are not limited to, fluoromethoxy, difluoromethoxy,trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc.

The term “carbonyl” or “carboxy” includes compounds and moieties whichcontain a carbon connected with a double bond to an oxygen atom, andtautomeric forms thereof. Examples of moieties that contain a carbonylinclude aldehydes, ketones, carboxylic acids, amides, esters,anhydrides, etc. The term “carboxy moiety” or “carbonyl moiety” refersto groups such as “alkylcarbonyl” groups wherein an alkyl group iscovalently bound to a carbonyl group, “alkenylcarbonyl” groups whereinan alkenyl group is covalently bound to a carbonyl group,“alkynylcarbonyl” groups wherein an alkynyl group is covalently bound toa carbonyl group, “arylcarbonyl” groups wherein an aryl group iscovalently attached to the carbonyl group. Furthermore, the term alsorefers to groups wherein one or more heteroatoms are covalently bondedto the carbonyl moiety. For example, the term includes moieties such as,for example, aminocarbonyl moieties, (wherein a nitrogen atom is boundto the carbon of the carbonyl group, e.g., an amide), aminocarbonyloxymoieties, wherein an oxygen and a nitrogen atom are both bond to thecarbon of the carbonyl group (e.g., also referred to as a “carbamate”).Furthermore, aminocarbonylamino groups (e.g., ureas) are also include aswell as other combinations of carbonyl groups bound to heteroatoms(e.g., nitrogen, oxygen, sulfur, etc. as well as carbon atoms).Furthermore, the heteroatom can be further substituted with one or morealkyl, alkenyl, alkynyl, aryl, aralkyl, acyl, etc. moieties.

The term “thiocarbonyl” or “thiocarboxy” includes compounds and moietieswhich contain a carbon connected with a double bond to a sulfur atom.The term “thiocarbonyl moiety” includes moieties that are analogous tocarbonyl moieties. For example, “thiocarbonyl” moieties includeaminothiocarbonyl, wherein an amino group is bound to the carbon atom ofthe thiocarbonyl group, furthermore other thiocarbonyl moieties include,oxythiocarbonyls (oxygen bound to the carbon atom),aminothiocarbonylamino groups, etc.

The term “ether” includes compounds or moieties that contain an oxygenbonded to two different carbon atoms or heteroatoms. For example, theterm includes “alkoxyalkyl” which refers to an alkyl, alkenyl, oralkynyl group covalently bonded to an oxygen atom that is covalentlybonded to another alkyl group.

The term “ester” includes compounds and moieties that contain a carbonor a heteroatom bound to an oxygen atom that is bonded to the carbon ofa carbonyl group. The term “ester” includes alkoxycarboxy groups such asmethoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl,pentoxycarbonyl, etc. The alkyl, alkenyl, or alkynyl groups are asdefined above.

The term “thioether” includes compounds and moieties which contain asulfur atom bonded to two different carbon or hetero atoms. Examples ofthioethers include, but are not limited to alkthioalkyls,alkthioalkenyls, and alkthioalkynyls. The term “alkthioalkyls” includecompounds with an alkyl, alkenyl, or alkynyl group bonded to a sulfuratom that is bonded to an alkyl group. Similarly, the term“alkthioalkenyls” and alkthioalkynyls” refer to compounds or moietieswherein an alkyl, alkenyl, or alkynyl group is bonded to a sulfur atomwhich is covalently bonded to an alkynyl group.

The term “hydroxy” or “hydroxyl” includes groups with an —OH or —O⁻.

The term “halogen” includes fluorine, bromine, chlorine, iodine, etc.The term “perhalogenated” generally refers to a moiety wherein allhydrogens are replaced by halogen atoms.

The terms “polycyclyl” or “polycyclic radical” include moieties with twoor more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, arylsand/or heterocyclyls) in which two or more carbons are common to twoadjoining rings, e.g., the rings are “fused rings”. Rings that arejoined through non-adjacent atoms are termed “bridged” rings. Each ofthe rings of the polycycle can be substituted with such substituents asdescribed above, as for example, halogen, hydroxyl, alkylcarbonyloxy,arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate,alkylcarbonyl, alkoxycarbonyl, alkylaminoacarbonyl,aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl,aralkylcarbonyl, alkenylcarbonyl, aminocarbonyl, alkylthiocarbonyl,alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (includingalkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino),acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyland ureido), amidino, imino, sulfhydryl, alkylthio, arylthio,thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl,sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkyl,alkylaryl, or an aromatic or heteroaromatic moiety.

The term “heteroatom” includes atoms of any element other than carbon orhydrogen. Preferred heteroatoms are nitrogen, oxygen, sulfur andphosphorus.

Additionally, the phrase “any combination thereof” implies that anynumber of the listed functional groups and molecules may be combined tocreate a larger molecular architecture. For example, the terms “phenyl,”“carbonyl” (or “═O”), “—O—,” “—OH,” and C₁₋₆ (i.e., —CH₃ and—CH₂CH₂CH₂—) can be combined to form a 3-methoxy-4-propoxybenzoic acidsubstituent. It is to be understood that when combining functionalgroups and molecules to create a larger molecular architecture,hydrogens can be removed or added, as required to satisfy the valence ofeach atom.

It is to be understood that all of the compounds of the inventiondescribed above will further include bonds between adjacent atoms and/orhydrogens as required to satisfy the valence of each atom. That is,bonds and/or hydrogen atoms are added to provide the following number oftotal bonds to each of the following types of atoms: carbon: four bonds;nitrogen: three bonds; oxygen: two bonds; and sulfur: two bonds.

Groups that are “optionally substituted” are unsubstituted or aresubstituted by other than hydrogen at one or more available positions,typically 1, 2, 3, 4 or 5 positions, by one or more suitable groups(which may be the same or different). Optional substitution is alsoindicated by the phrase “substituted with from 0 to X substituents,”where X is the maximum number of possible substituents. Certainoptionally substituted groups are substituted with from 0 to 2, 3 or 4independently selected substituents (i.e., are unsubstituted orsubstituted with up to the recited maximum number of substitutents).

It will be noted that the structures of some of the compounds of thisinvention include asymmetric carbon atoms. It is to be understoodaccordingly that the isomers arising from such asymmetry (e.g., allenantiomers, stereoisomers, rotamers, tautomers, diastereomers, orracemates) are included within the scope of this invention. Such isomerscan be obtained in substantially pure form by classical separationtechniques and by stereochemically controlled synthesis. Furthermore,the structures and other compounds and moieties discussed in thisapplication also include all tautomers thereof. Compounds describedherein may be obtained through art recognized synthesis strategies.

It will also be noted that the substituents of some of the compounds ofthis invention include isomeric cyclic structures. It is to beunderstood accordingly that constitutional isomers of particularsubstituents are included within the scope of this invention, unlessindicated otherwise. For example, the term “tetrazole” includestetrazole, 2H-tetrazole, 3H-tetrazole, 4H-tetrazole and 5H-tetrazole.

Use in HCV-Associated Disorders

The compounds of the present invention have valuable pharmacologicalproperties and are useful in the treatment of diseases. In certainembodiments, compounds of the invention are useful in the treatment ofHCV-associated disorders, e.g., as drugs to treat HCV infection.

The term “use” includes any one or more of the following embodiments ofthe invention, respectively: the use in the treatment of HCV-associateddisorders; the use for the manufacture of pharmaceutical compositionsfor use in the treatment of these diseases, e.g., in the manufacture ofa medicament; methods of use of compounds of the invention in thetreatment of these diseases; pharmaceutical preparations havingcompounds of the invention for the treatment of these diseases; andcompounds of the invention for use in the treatment of these diseases;as appropriate and expedient, if not stated otherwise. In particular,diseases to be treated and are thus preferred for use of a compound ofthe present invention are selected from HCV-associated disorders,including those corresponding to HCV-infection, as well as thosediseases that depend on the activity of one or more of the NS3, NS4A,NS4B, NS5A and NS5B proteins, or a NS3-NS4A, NS4A-NS4B, NS4B-NS5A orNS5A-NS5B complex. The term “use” further includes embodiments ofcompositions herein which bind to an HCV protein sufficiently to serveas tracers or labels, so that when coupled to a fluor or tag, or maderadioactive, can be used as a research reagent or as a diagnostic or animaging agent.

In certain embodiments, a compound of the present invention is used fortreating HCV-associated diseases, and use of the compound of the presentinvention as an inhibitor of any one or more HCVs. It is envisioned thata use can be a treatment of inhibiting one or more strains of HCV.

Assays

The inhibition of HCV activity may be measured as using a number ofassays available in the art. An example of such an assay can be found inAnal Biochem. 1996 240(1): 60-7; which is incorporated by reference inits entirety. Assays for measurement of HCV activity are also describedin the experimental section below.

Pharmaceutical Compositions

The language “effective amount” of the compound is that amount necessaryor sufficient to treat or prevent an HCV-associated disorder, e.g.prevent the various morphological and somatic symptoms of anHCV-associated disorder, and/or a disease or condition described herein.In an example, an effective amount of the HCV-modulating compound is theamount sufficient to treat HCV infection in a subject. In anotherexample, an effective amount of the HCV-modulating compound is theamount sufficient to treat HCV infection, liver cirrhosis, chronic liverdisease, hepatocellular carcinoma, cryoglobulinaemia, non-Hodgkin'slymphoma, and a suppressed innate intracellular immune response in asubject. The effective amount can vary depending on such factors as thesize and weight of the subject, the type of illness, or the particularcompound of the invention. For example, the choice of the compound ofthe invention can affect what constitutes an “effective amount.” One ofordinary skill in the art would be able to study the factors containedherein and make the determination regarding the effective amount of thecompounds of the invention without undue experimentation.

The regimen of administration can affect what constitutes an effectiveamount. The compound of the invention can be administered to the subjecteither prior to or after the onset of an HCV-associated state. Further,several divided dosages, as well as staggered dosages, can beadministered daily or sequentially, or the dose can be continuouslyinfused, or can be a bolus injection. Further, the dosages of thecompound(s) of the invention can be proportionally increased ordecreased as indicated by the exigencies of the therapeutic orprophylactic situation.

Compounds of the invention may be used in the treatment of states,disorders or diseases as described herein, or for the manufacture ofpharmaceutical compositions for use in the treatment of these diseases.Methods of use of compounds of the present invention in the treatment ofthese diseases, or pharmaceutical preparations having compounds of thepresent invention for the treatment of these diseases.

The language “pharmaceutical composition” includes preparations suitablefor administration to mammals, e.g., humans. When the compounds of thepresent invention are administered as pharmaceuticals to mammals, e.g.,humans, they can be given per se or as a pharmaceutical compositioncontaining, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) ofactive ingredient in combination with a pharmaceutically acceptablecarrier.

The phrase “pharmaceutically acceptable carrier” is art recognized andincludes a pharmaceutically acceptable material, composition or vehicle,suitable for administering compounds of the present invention tomammals. The carriers include liquid or solid filler, diluent,excipient, solvent or encapsulating material, involved in carrying ortransporting the subject agent from one organ, or portion of the body,to another organ, or portion of the body. Each carrier must be“acceptable” in the sense of being compatible with the other ingredientsof the formulation and not injurious to the patient. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude: sugars, such as lactose, glucose and sucrose; starches, such ascorn starch and potato starch; cellulose, and its derivatives, such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients, such as cocoabutter and suppository waxes; oils, such as peanut oil, cottonseed oil,safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols,such as propylene glycol; polyols, such as glycerin, sorbitol, mannitoland polyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; and other non-toxiccompatible substances employed in pharmaceutical formulations.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like;oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, α-tocopherol, and the like; and metal chelating agents, such ascitric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaricacid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient that canbe combined with a carrier material to produce a single dosage form willgenerally be that amount of the compound that produces a therapeuticeffect. Generally, out of one hundred percent, this amount will rangefrom about 1 percent to about ninety-nine percent of active ingredient,preferably from about 5 percent to about 70 percent, most preferablyfrom about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules and the like), theactive ingredient is mixed with one or more pharmaceutically acceptablecarriers, such as sodium citrate or dicalcium phosphate, and/or any ofthe following: fillers or extenders, such as starches, lactose, sucrose,glucose, mannitol, and/or silicic acid; binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as, for example,cetyl alcohol and glycerol monostearate; absorbents, such as kaolin andbentonite clay; lubricants, such a talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof; and coloring agents. In the case of capsules, tabletsand pills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions that can bedissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containopacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions that can be used include polymeric substances andwaxes. The active ingredient can also be in micro-encapsulated form, ifappropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluent commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically acceptablecarrier, and with any preservatives, buffers, or propellants that may berequired.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the activecompound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacteriostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers that may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents, such as sugars, sodium chloride,and the like into the compositions. In addition, prolonged absorption ofthe injectable pharmaceutical form may be brought about by the inclusionof agents that delay absorption such as aluminum monostearate andgelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions that are compatible with body tissue.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given by formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc., administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administration is preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion of theparticular compound being employed, the duration of the treatment, otherdrugs, compounds and/or materials used in combination with theparticular compound employed, the age, sex, weight, condition, generalhealth and prior medical history of the patient being treated, and likefactors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound that is the lowest dose effective to producea therapeutic effect. Such an effective dose will generally depend uponthe factors described above. Generally, intravenous and subcutaneousdoses of the compounds of this invention for a patient, when used forthe indicated analgesic effects, will range from about 0.0001 to about100 mg per kilogram of body weight per day, more preferably from about0.01 to about 50 mg per kg per day, and still more preferably from about1.0 to about 100 mg per kg per day. An effective amount is that amounttreats an HCV-associated disorder.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms.

While it is possible for a compound of the present invention to beadministered alone, it is preferable to administer the compound as apharmaceutical composition.

Synthetic Procedure

Compounds of the present invention are prepared from commonly availablecompounds using procedures known to those skilled in the art, includingany one or more of the following conditions without limitation:

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group,” unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such ase.g., Science of Synthesis: Houben-Weyl Methods of MolecularTransformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pp.(URL: http://www.science-of-synthesis.com (Electronic Version, 48Volumes)); J. F. W. McOmie, “Protective Groups in Organic Chemistry”,Plenum Press, London and New York 1973, in T. W. Greene and P. G. M.Wuts, “Protective Groups in Organic Synthesis”, Third edition, Wiley,New York 1999, in “The Peptides”; Volume 3 (editors: E. Gross and J.Meienhofer), Academic Press, London and New York 1981, in “Methoden derorganischen Chemie” (Methods of Organic Chemistry), Houben Weyl, 4thedition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H.-D.Jakubke and H. Jeschkeit, “Aminosauren, Peptide, Proteine” (Amino acids,Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharideand Derivate” (Chemistry of Carbohydrates: Monosaccharides andDerivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic ofprotecting groups is that they can be removed readily (i.e., without theoccurrence of undesired secondary reactions) for example by solvolysis,reduction, photolysis or alternatively under physiological conditions(e.g., by enzymatic cleavage).

Salts of compounds of the present invention having at least onesalt-forming group may be prepared in a manner known per se. Forexample, salts of compounds of the present invention having acid groupsmay be formed, for example, by treating the compounds with metalcompounds, such as alkali metal salts of suitable organic carboxylicacids, e.g., the sodium salt of 2-ethylhexanoic acid, with organicalkali metal or alkaline earth metal compounds, such as thecorresponding hydroxides, carbonates or hydrogen carbonates, such assodium or potassium hydroxide, carbonate or hydrogen carbonate, withcorresponding calcium compounds or with ammonia or a suitable organicamine, stoichiometric amounts or only a small excess of the salt-formingagent preferably being used. Acid addition salts of compounds of thepresent invention are obtained in customary manner, e.g., by treatingthe compounds with an acid or a suitable anion exchange reagent.Internal salts of compounds of the present invention containing acid andbasic salt-forming groups, e.g., a free carboxy group and a free aminogroup, may be formed, e.g., by the neutralisation of salts, such as acidaddition salts, to the isoelectric point, e.g., with weak bases, or bytreatment with ion exchangers.

Salts can be converted in customary manner into the free compounds;metal and ammonium salts can be converted, for example, by treatmentwith suitable acids, and acid addition salts, for example, by treatmentwith a suitable basic agent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known per se into the individual isomers;diastereoisomers can be separated, for example, by partitioning betweenpolyphasic solvent mixtures, recrystallisation and/or chromatographicseparation, for example over silica gel or by, e.g., medium pressureliquid chromatography over a reversed phase column, and racemates can beseparated, for example, by the formation of salts with optically puresalt-forming reagents and separation of the mixture of diastereoisomersso obtainable, for example by means of fractional crystallisation, or bychromatography over optically active column materials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g., using chromatographic methods,distribution methods, (re-) crystallization, and the like.

General Process Conditions

The following applies in general to all processes mentioned throughoutthis disclosure.

The process steps to synthesize the compounds of the invention can becarried out under reaction conditions that are known per se, includingthose mentioned specifically, in the absence or, customarily, in thepresence of solvents or diluents, including, for example, solvents ordiluents that are inert towards the reagents used and dissolve them, inthe absence or presence of catalysts, condensation or neutralizingagents, for example ion exchangers, such as cation exchangers, e.g., inthe H⁺ form, depending on the nature of the reaction and/or of thereactants at reduced, normal or elevated temperature, for example in atemperature range of from about −100° C. to about 190° C., including,for example, from approximately −80° C. to approximately 150° C., forexample at from −80 to −60° C., at room temperature, at from −20 to 40°C. or at reflux temperature, under atmospheric pressure or in a closedvessel, where appropriate under pressure, and/or in an inert atmosphere,for example under an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers, for example analogously tothe methods described in Science of Synthesis: Houben-Weyl Methods ofMolecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofurane ordioxane, liquid aromatic hydrocarbons, such as benzene or toluene,alcohols, such as methanol, ethanol or 1- or 2-propanol, nitriles, suchas acetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, or mixtures of those solvents, for example aqueoussolutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

Pro-Drugs

The present invention also relates to pro-drugs of a compound of thepresent invention that are converted in vivo to the compounds of thepresent invention as described herein. Any reference to a compound ofthe present invention is therefore to be understood as referring also tothe corresponding pro-drugs of the compound of the present invention, asappropriate and expedient.

Combinations

A compound of the present invention may also be used in combination withother agents, e.g., an additional HCV-modulating compound that is or isnot of the formula I, for treatment of and HCV-associated disorder in asubject.

By the term “combination”, is meant either a fixed combination in onedosage unit form, or a kit of parts for the combined administrationwhere a compound of the present invention and a combination partner maybe administered independently at the same time or separately within timeintervals that especially allow that the combination partners show acooperative, e.g., synergistic, effect, or any combination thereof.

For example, WO 2005/042020, incorporated herein by reference in itsentirety, describes the combination of various HCV inhibitors with acytochrome P450 (“CYP”) inhibitor. Any CYP inhibitor that improves thepharmacokinetics of the relevant NS3/4A protease may be used incombination with the compounds of this invention. These CYP inhibitorsinclude, but are not limited to, ritonavir (WO 94/14436, incorporatedherein by reference in its entirety), ketoconazole, troleandomycin,4-methylpyrazole, cyclosporin, clomethiazole, cimetidine, itraconazole,fluconazole, miconazole, fluvoxamine, fluoxetine, nefazodone,sertraline, indinavir, nelfinavir, amprenavir, fosamprenavir,saquinavir, lopinavir, delavirdine, erythromycin, VX-944, and VX-497.Preferred CYP inhibitors include ritonavir, ketoconazole,troleandomycin, 4-methylpyrazole, cyclosporin, and clomethiazole.

Methods for measuring the ability of a compound to inhibit CYP activityare known (see, e.g., U.S. Pat. No. 6,037,157 and Yun, et al. DrugMetabolism & Disposition, vol. 21, pp. 403-407 (1993); incorporatedherein by reference). For example, a compound to be evaluated may beincubated with 0.1, 0.5, and 1.0 mg protein/ml, or other appropriateconcentration of human hepatic microsomes (e.g., commercially available,pooled characterized hepatic microsomes) for 0, 5, 10, 20, and 30minutes, or other appropriate times, in the presence of anNADPH-generating system. Control incubations may be performed in theabsence of hepatic microsomes for 0 and 30 minutes (triplicate). Thesamples may be analyzed for the presence of the compound. Incubationconditions that produce a linear rate of compound metabolism will beused a guide for further studies. Experiments known in the art can beused to determine the kinetics of the compound metabolism (K_(m) andV_(max)). The rate of disappearance of compound may be determined andthe data analyzed according to Michaelis-Menten kinetics by usingLineweaver-Burk, Eadie-Hofstee, or nonlinear regression analysis.

Inhibition of metabolism experiments may then be performed. For example,a compound (one concentration, <K_(m)) may be incubated with pooledhuman hepatic microsomes in the absence or presence of a CYP inhibitor(such as ritonavir) under the conditions determined above. As would berecognized, control incubations should contain the same concentration oforganic solvent as the incubations with the CYP inhibitor. Theconcentrations of the compound in the samples may be quantitated, andthe rate of disappearance of parent compound may be determined, withrates being expressed as a percentage of control activity.

Methods for evaluating the influence of co-administration of a compoundof the invention and a CYP inhibitor in a subject are also known (see,e.g., US2004/0028755; incorporated herein by reference). Any suchmethods could be used in connection with this invention to determine thepharmacokinetic impact of a combination. Subjects that would benefitfrom treatment according to this invention could then be selected.

Accordingly, one embodiment of this invention provides a method foradministering an inhibitor of CYP3A4 and a compound of the invention.Another embodiment of this invention provides a method for administeringan inhibitor of isozyme 3A4 (“CYP3A4”), isozyme 2C19 (“CYP2C19”),isozyme 2D6 (“CYP2D6”), isozyme 1A2 (“CYP1A2”), isozyme 2C9 (“CYP2C9”),or isozyme 2E1 (“CYP2E1”). In embodiments where the protease inhibitoris VX-950 (or a sterereoisomer thereof), the CYP inhibitor preferablyinhibits CYP3A4.

As would be appreciated, CYP3A4 activity is broadly observed in humans.Accordingly, embodiments of this invention involving inhibition ofisozyme 3A4 would be expected to be applicable to a broad range ofpatients.

Accordingly, this invention provides methods wherein the CYP inhibitoris administered together with the compound of the invention in the samedosage form or in separate dosage forms.

The compounds of the invention (e.g., compound of Formula I orsubformulae thereof) may be administered as the sole ingredient or incombination or alteration with other antiviral agents, especially agentsactive against HCV. In combination therapy, effective dosages of two ormore agents are administered together, whereas in alternation orsequential-step therapy, an effective dosage of each agent isadministered serially or sequentially. In general, combination therapyis typically preferred over alternation therapy because it inducesmultiple simultaneous stresses on the virus. The dosages given willdepend on absorption, inactivation and excretion rate of the drug aswell as other factors. It is to be noted that dosage values will alsovary with the severity of the condition to be alleviated. It is to befurther understood that for any particular subject, specific dosageregimens and schedules should be adjusted over time according to theindividual need and the professional judgment of the personadministering or supervising the administration of the compositions. Theefficacy of a drug against the viral infection can be prolonged,augmented, or restored by administering the compound in combination oralternation with a second, and perhaps third antiviral compound thatinduces a different gene mutation than that caused by the principle drugin a drug resistant virus. Alternatively, the pharmacokinetic,biodistribution or other parameters of the drug can be altered by suchcombination or alternation therapy.

Daily dosages required in practicing the method of the present inventionwill vary depending upon, for example, the compound of the inventionemployed, the host, the mode of administration, the severity of thecondition to be treated. A preferred daily dosage range is about from 1to 50 mg/kg per day as a single dose or in divided doses. Suitable dailydosages for patients are on the order of from e.g. 1 to 20 mg/kg p.o ori.v. Suitable unit dosage forms for oral administration comprise fromca. 0.25 to 10 mg/kg active ingredient, e.g. compound of Formula I orany subformulae thereof, together with one or more pharmaceuticallyacceptable diluents or carriers therefor. The amount of co-agent in thedosage form can vary greatly, e.g., 0.00001 to 1000 mg/kg activeingredient.

Daily dosages with respect to the co-agent used will vary dependingupon, for example, the compound employed, the host, the mode ofadministration and the severity of the condition to be treated. Forexample, lamivudine may be administered at a daily dosage of 100 mg. Thepegylated interferon may be administered parenterally one to three timesper week, preferably once a week, at a total weekly dose ranging from 2to 10 million IU, more preferable 5 to 10 million IU, most preferable 8to 10 million IU. Because of the diverse types of co-agent that may beused, the amounts can vary greatly, e.g., 0.0001 to 5,000 mg/kg per day.

The current standard of care for treating hepatitis C is the combinationof pegylated interferon alpha with ribavirin, of which the recommendeddoses are 1.5 μg/kg/wk peginterferon alfa-2b or 180 μg/wk peginterferonalfa-2a, plus 1,000 to 1,200 mg daily of ribavirin for 48 weeks forgenotype I patients, or 800 mg daily of ribavirin for 24 weeks forgenotype 2/3 patients.

The compound of the invention (e.g., compound of Formula I orsubformulae thereof) and co-agents of the invention may be administeredby any conventional route, in particular enterally, e.g. orally, forexample in the form of solutions for drinking, tablets or capsules orparenterally, for example in the form of injectable solutions orsuspensions. Certain preferred pharmaceutical compositions may be e.g.those based on microemulsions as described in UK 2,222,770 A.

The compound of the invention (e.g., compound of Formula I orsubformulae thereof) are administered together with other drugs(co-agents) e.g. a drug which has anti-viral activity, especiallyanti-Flaviviridae activity, most especially anti-HCV activity, e.g. aninterferon, e.g. interferon-α-2a or interferon-α-2b, e.g. Intron® A,Roferon®, Avonex®, Rebif® or Betaferon®, or an interferon conjugated toa water soluble polymer or to human albumin, e.g. albuferon, ananti-viral agent, e.g. ribavirin, lamivudine, the compounds disclosed inU.S. Pat. No. 6,812,219 and WO 2004/002422 A2 (the disclosures of whichare incorporated herein by reference in their entireties), an inhibitorof the HCV or other Flaviviridae virus encoded factors like the NS3/4Aprotease, helicase or RNA polymerase or a prodrug of such an inhibitor,an anti-fibrotic agent, e.g. a N-phenyl-2-pyrimidine-amine derivative,e.g. imatinib, an immune modulating agent, e.g. mycophenolic acid, asalt or a prodrug thereof, e.g. sodium mycophenolate or mycophenolatemofetil, or a S1P receptor agonist, e.g. FTY720 or an analogue thereofoptionally phosphorylated, e.g. as disclosed in EP627406A1, EP778263A1,EP1002792A1, WO02/18395, WO02/76995, WO 02/06268, JP2002316985,WO03/29184, WO03/29205, WO03/62252 and WO03/62248, the disclosures ofwhich are incorporated herein by reference in their entireties.

Conjugates of interferon to a water-soluble polymer are meant to includeespecially conjugates to polyalkylene oxide homopolymers such aspolyethylene glycol (PEG) or polypropylene glycols, polyoxyethylenatedpolyols, copolymers thereof and block copolymers thereof. As analternative to polyalkylene oxide-based polymers, effectivelynon-antigenic materials such as dextran, polyvinyl pyrrolidones,polyacrylamides, polyvinyl alcohols, carbohydrate-based polymers and thelike can be used. Such interferon-polymer conjugates are described inU.S. Pat. Nos. 4,766,106, 4,917,888, European Patent Application No. 0236 987, European Patent Application No. 0 510 356 and InternationalApplication Publication No. WO 95/13090, the disclosures of which areincorporated herein by reference in their entireties. Since thepolymeric modification sufficiently reduces antigenic responses, theforeign interferon need not be completely autologous. Interferon used toprepare polymer conjugates may be prepared from a mammalian extract,such as human, ruminant or bovine interferon, or recombinantly produced.Preferred are conjugates of interferon to polyethylene glycol, alsoknown as pegylated interferons.

Especially preferred conjugates of interferon are pegylatedalfa-interferons, for example pegylated interferon-α-2a, pegylatedinterferon-α-2b; pegylated consensus interferon or pegylated purifiedinterferon-α product. Pegylated interferon-α-2a is described e.g. inEuropean Patent 593,868 (incorporated herein by reference in itsentirety) and commercially available e.g. under the tradename PEGASYS®(Hoffmann-La Roche). Pegylated interferon-α-2b is described, e.g. inEuropean Patent 975,369 (incorporated herein by reference in itsentirety) and commercially available e.g. under the tradename PEG-INTRONA® (Schering Plough). Pegylated consensus interferon is described in WO96/11953 (incorporated herein by reference in its entirety). Thepreferred pegylated α-interferons are pegylated interferon-α-2a andpegylated interferon-α-2b. Also preferred is pegylated consensusinterferon.

Other preferred co-agents are fusion proteins of an interferon, forexample fusion proteins of interferon-α-2a, interferon-α-2b; consensusinterferon or purified interferon-α product, each of which is fused withanother protein. Certain preferred fusion proteins comprise aninterferon (e.g., interferon-α-2b) and an albumin as described in U.S.Pat. No. 6,973,322 and international publications WO02/60071,WO05/003296 and WO05/077042 (Human Genome Sciences). A preferredinterferon conjugated to a human albumin is Albuferon (Human GenomeSciences).

Cyclosporins which bind strongly to cyclophilin but are notimmunosuppressive include those cyclosporins recited in U.S. Pat. Nos.5,767,069 and 5,981,479 and are incorporated herein by reference.MeIle⁴-Cyclosporin is a preferred non-immunosuppressive cyclosporin.Certain other cyclosporin derivatives are described in WO2006039668(Scynexis) and WO2006038088 (Debiopharm SA) and are incorporated hereinby reference. A cyclosporin is considered to be non-immunosuppressivewhen it has an activity in the Mixed Lymphocyte Reaction (MLR) of nomore than 5%, preferably no more than 2%, that of cyclosporin A. TheMixed Lymphocyte Reaction is described by T. Meo in “ImmunologicalMethods”, L. Lefkovits and B. Penis, Eds., Academic Press, N.Y. pp.227-239 (1979). Spleen cells (0.5×10⁶) from Balb/c mice (female, 8-10weeks) are co-incubated for 5 days with 0.5×10⁶ irradiated (2000 rads)or mitomycin C treated spleen cells from CBA mice (female, 8-10 weeks).The irradiated allogeneic cells induce a proliferative response in theBalb c spleen cells which can be measured by labeled precursorincorporation into the DNA. Since the stimulator cells are irradiated(or mitomycin C treated) they do not respond to the Balb/c cells withproliferation but do retain their antigenicity. The IC₅₀ found for thetest compound in the MLR is compared with that found for cyclosporin Ain a parallel experiment. In addition, non-immunosuppressivecyclosporins lack the capacity of inhibiting CN and the downstream NF-ATpathway. [MeIle]⁴-ciclosporin is a preferred non-immunosuppressivecyclophilin-binding cyclosporin for use according to the invention.

Ribavirin (1-β-D-ribofuranosyl-1-1,2,4-triazole-3-caroxamide) is asynthetic, non-interferon-inducing, broad spectrum antiviral nucleosideanalog sold under the trade name, Virazole (The Merck Index, 11^(th)edition, Editor: Budavar, S, Merck & Co., Inc., Rahway, N.J., p1304,1989). U.S. Pat. No. 3,798,209 and RE29,835 (incorporated herein byreference in their entireties) disclose and claim ribavirin. Ribavirinis structurally similar to guanosine, and has in vitro activity againstseveral DNA and RNA viruses including Flaviviridae (Gary L. Davis,Gastroenterology 118:S104-S114, 2000).

Ribavirin reduces serum amino transferase levels to normal in 40% ofpatients, but it does not lower serum levels of HCV-RNA (Gary L. Davis,Gastroenterology 118:S104-S114, 2000). Thus, ribavirin alone is noteffective in reducing viral RNA levels. Additionally, ribavirin hassignificant toxicity and is known to induce anemia. Ribavirin is notapproved for monotherapy against HCV; it is approved in combination withinterferon alpha-2a or interferon alpha-2b for the treatment of HCV.

A further preferred combination is a combination of a compound of theinvention (e.g., a compound of Formula I or any subformulae thereof)with a non-immunosuppressive cyclophilin-binding cyclosporine, withmycophenolic acid, a salt or a prodrug thereof, and/or with a S1Preceptor agonist, e.g. FTY720.

Additional examples of compounds that can be used in combination oralternation treatments include:

(1) Interferons, including interferon alpha 2a or 2b and pegylated (PEG)interferon alpha 2a or 2b, for example:

-   -   (a) Intron-A®, interferon alfa-2b (Schering Corporation,        Kenilworth, N.J.);    -   (b) PEG-Intron®, peginteferon alfa-2b (Schering Corporation,        Kenilworth, N.J.);    -   (c) Roferon®, recombinant interferon alfa-2a (Hoffmann-La Roche,        Nutley, N.J.);    -   (d) Pegasys®, peginterferon alfa-2a (Hoffmann-La Roche, Nutley,        N.J.);    -   (e) Berefor®, interferon alfa 2 available (Boehringer Ingelheim        Pharmaceutical, Inc., Ridgefield, Conn.);    -   (f) Sumiferon®, a purified blend of natural alpha interferons        (Sumitomo, Japan)    -   (g) Wellferon®, lymphoblastoid interferon alpha n1        (GlaxoSmithKline);    -   (h) Infergen®, consensus alpha interferon (InterMune        Pharmaceuticals, Inc., Brisbane, Calif.);    -   (i) Alferon®, a mixture of natural alpha interferons (Interferon        Sciences, and Purdue Frederick Co., CT);    -   (j) Viraferon®;    -   (k) Consensus alpha interferon from Amgen, Inc., Newbury Park,        Calif.,

Other forms of interferon include: interferon beta, gamma, tau andomega, such as Rebif (Interferon beta 1a) by Serono, Omniferon (naturalinterferon) by Viragen, REBIF (interferon beta-1a) by Ares-Serono, OmegaInterferon by BioMedicines; oral Interferon Alpha by AmarilloBiosciences; an interferon conjugated to a water soluble polymer or to ahuman albumin, e.g., Albuferon (Human Genome Sciences), an antiviralagent, a consensus interferon, ovine or bovine interferon-tau

Conjugates of interferon to a water-soluble polymer are meant to includeespecially conjugates to polyalkylene oxide homopolymers such aspolyethylene glocol (PEG) or polypropylene glycols, polyoxyethylenatedpolyols, copolymers thereof and block copolymers thereof. As analternative to polyalkylene oxid-based polymers, effectivelynon-antigenic materials such as dextran, polyvinyl pyrrolidones,polyacrylamides, polyvinyl alcohols, carbohydrate-based polymers and thelike can be used. Since the polymeric modification sufficiently reducesantigenic response, the foreign interferon need not be completelyautologous. Interferon used to prepare polymer conjugates may beprepared from a mammalian extract, such as human, ruminant or bovineinterferon, or recombinantly produced. Preferred are conjugates ofinterferon to polyethylene glycol, also known as pegylated interferons.

(2) Ribavirin, such as ribavirin(1-beta-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) from ValeantPharmaceuticals, Inc., Costa Mesa, Calif.); Rebetol® from ScheringCorporation, Kenilworth, N.J., and Copegus® from Hoffmann-La Roche,Nutley, N.J.; and new ribavirin analogues in development such asLevovirin and Viramidine by Valeant,

(3) Thiazolidine derivatives which show relevant inhibition in areverse-phase HPLC assay with an NS3/4A fusion protein and NS5A/5Bsubstrate (Sudo K. et al., Antiviral Research, 1996, 32, 9-18),especially compound RD-1-6250, possessing a fused cinnamoyl moietysubstituted with a long alkyl chain, RD4 6205 and RD4 6193;

(4) Thiazolidines and benzanilides identified in Kakiuchi N. et al. J.FEBS Letters 421, 217-220; Takeshita N. et al. Analytical Biochemistry,1997, 247, 242-246;

(5) A phenan-threnequinone possessing activity against protease in aSDS-PAGE and autoradiography assay isolated from the fermentationculture broth of Streptomyces sp., Sch 68631 (Chu M. et al., TetrahedronLetters, 1996, 37, 7229-7232), and Sch 351633, isolated from the fungusPenicillium griseofulvum, which demonstrates activity in a scintillationproximity assay (Chu M. et al, Bioorganic and Medicinal ChemistryLetters 9, 1949-1952);

(6) Protease inhibitors.

Examples include substrate-based NS3 protease inhibitors (Attwood etal., Antiviral peptide derivatives, PCT WO 98/22496, 1998; Attwood etal., Antiviral Chemistry and Chemotherapy 1999, 10, 259-273; Attwood etal, Preparation and use of amino acid derivatives as anti-viral agents,German Patent Pub. DE 19914474; Tung et al. Inhibitors of serineproteases, particularly hepatitis C virus NS3 protease; PCT WO98/17679), including alphaketoamides and hydrazinoureas, and inhibitorsthat terminate in an electrophile such as a boronic acid or phosphonate(Llinas-Brunet et al. Hepatitis C inhibitor peptide analogues, PCT WO99/07734) are being investigated.

Non-substrate-based NS3 protease inhibitors such as2,4,6-trihydroxy-3-nitro-benzamide derivatives (Sudo K. et al.,Biochemical and Biophysical Research Communications, 1997, 238 643-647;Sudo K. et al. Antiviral Chemistry and Chemotherapy, 1998, 9, 186),including RD3-4082 and RD3-4078, the former substituted on the amidewith a 14 carbon chain and the latter processing a para-phenoxyphenylgroup are also being investigated.

Sch 68631, a phenanthrenequinone, is an HCV protease inhibitor (Chu M etal., Tetrahedron Letters 37:7229-7232, 1996). In another example by thesame authors, Sch 351633, isolated from the fungus Penicilliumgrieofulvum, was identified as a protease inhibitor (Chu M. et al.,Bioorganic and Medicinal Chemistry Letters 9:1949-1952). Nanomolarpotency against the HCV NS3 protease enzyme has been achieved by thedesign of selective inhibitors based on the macromolecule eglin c. Eglinc, isolated from leech, is a potent inhibitor of several serineproteases such as S. griseus proteases A and B, ∀-chymotrypsin, chymaseand subtilisin. Qasim M. A. et al., Biochemistry 36:1598-1607, 1997.

U.S. patents disclosing protease inhibitors for the treatment of HCVinclude, for example, U.S. Pat. No. 6,004,933 to Spruce et al(incorporated herein by reference in its entirety) which discloses aclass of cysteine protease inhibitors for inhibiting HCV endopeptidase2; U.S. Pat. No. 5,990,276 to Zhang et al. (incorporated herein byreference in its entirety) which discloses synthetic inhibitors ofhepatitis C virus NS3 protease; U.S. Pat. No. 5,538,865 to Reyes et al.(incorporated herein by reference in its entirety). Peptides as NS3serine protease inhibitors of HCV are disclosed in WO 02/008251 toCorvas International, Inc., and WO 02/08187 and WO 02/008256 to ScheringCorporation (incorporated herein by reference in their entireties). HCVinhibitor tripeptides are disclosed in U.S. Pat. Nos. 6,534,523,6,410,531 and 6,420,380 to Boehringer Ingelheim and WO 02/060926 toBristol Myers Squibb (incorporated herein by reference in theirentireties). Diaryl peptides as NS3 serine protease inhibitors of HCVare disclosed in WO 02/48172 to Schering Corporation (incorporatedherein by reference). Imidazoleidinones as NS3 serine proteaseinhibitors of HCV are disclosed in WO 02/18198 to Schering Corporationand WO 02/48157 to Bristol Myers Squibb (incorporated herein byreference in their entireties). WO 98/17679 to Vertex Pharmaceuticalsand WO 02/48116 to Bristol Myers Squibb also disclose HCV proteaseinhibitors (incorporated herein by reference in their entireties).

HCV NS3-4A serine protease inhibitors including BILN 2061 by BoehringerIngelheim, VX-950 by Vertex, SCH 6/7 by Schering-Plough, and othercompounds currently in preclinical development;

Substrate-based NS3 protease inhibitors, including alphaketoamides andhydrazinoureas, and inhibitors that terminate in an elecrophile such asa boronic acid or phosphonate; Non-substrate-based NS3 proteaseinhibitors such as 2,4,6-trihydroxy-3-nitro-benzamide derivativesincluding RD3-4082 and RD3-4078, the former substituted on the amidewith a 14 carbon chain and the latter processing a para-phenoxyphenylgroup; and Sch68631, a phenanthrenequinone, an HCV protease inhibitor.

Sch 351633, isolated from the fungus Penicillium griseofulvum wasidentified as a protease inhibitor. Eglin c, isolated from leech is apotent inhibitor of several serine proteases such as S. griseusproteases A and B, a-chymotrypsin, chymase and subtilisin.

U.S. Pat. No. 6,004,933 (incorporated herein by reference in itsentirety) discloses a class of cysteine protease inhibitors frominhibiting HCV endopeptidase 2; synthetic inhibitors of HCV NS3 protease(pat), HCV inhibitor tripeptides (pat), diaryl peptides such as NS3serine protease inhibitors of HCV (pat), Imidazolidindiones as NS3serine protease inhibitors of HCV (pat).

Thiazolidines and benzanilides (ref). Thiazolidine derivatives whichshow relevant inhibition in a reverse-phase HPLC assay with an NS3/4Afusion protein and NS5A/5B substrate especially compound RD-16250possessing a fused cinnamoyl moiety substituted with a long alkyl chain,RD4 6205 and RD4 6193

Phenan-threnequinone possessing activity against protease in a SDS-PAGEand autoradiography assay isolated from the fermentation culture brothof Streptomyces sp, Sch68631 and Sch351633, isolated from the fungusPenicillium griseofulvum, which demonstrates activity in a scintillationproximity assay.

(7) Nucleoside or non-nucleoside inhibitors of HCV NS5B RNA-dependentRNA polymerase, such as 2′-C-methyl-3′-O-L-valine ester ribofuranosylcytidine (Idenix) as disclosed in WO 2004/002422 A2 (incorporated hereinby reference in its entirety), R803 (Rigel), JTK-003 (Japan Tabacco),HCV-086 (ViroPharma/Wyeth) and other compounds currently in preclinicaldevelopment;

gliotoxin (ref) and the natural product cerulenin;

2′-fluoronucleosides;

other nucleoside analogues as disclosed in WO 02/057287 A2, WO 02/057425A2, WO 01/90121, WO 01/92282, and U.S. Pat. No. 6,812,219, thedisclosures of which are incorporated herein by reference in theirentirety.

Idenix Pharmaceuticals discloses the use of branched nucleosides in thetreatment of flaviviruses (including HCV) and pestiviruses inInternational Publication Nos. WO 01/90121 and WO 01/92282 (incorporatedherein by reference in their entireties). Specifically, a method for thetreatment of hepatitis C infection (and flaviviruses and pestiviruses)in humans and other host animals is disclosed in the Idenix publicationsthat includes administering an effective amount of a biologically activel′, 2′, 3′ or 4′-branced B-D or B-L nucleosides or a pharmaceuticallyacceptable salt or prodrug thereof, administered either alone or incombination with another antiviral agent, optionally in apharmaceutically acceptable carrier. Certain preferred biologicallyactive 1′, 2′, 3′, or 4′ branched B-D or B-L nucleosides, includingTelbivudine, are described in U.S. Pat. Nos. 6,395,716 and 6,875,751,each of which are incorporated herein by reference.

Other patent applications disclosing the use of certain nucleosideanalogs to treat hepatitis C virus include: PCTCA00/01316 (WO 01/32153;filed Nov. 3, 2000) and PCT/CA01/00197 (WO 01/60315; filed Feb. 19,2001) filed by BioChem Pharma, Inc., (now Shire Biochem, Inc.);PCT/US02/01531 (WO 02/057425; filed Jan. 18, 2002) and PCT/US02/03086(WO 02/057287; filed Jan. 18, 2002) filed by Merck & Co., Inc.,PCT/EP01/09633 (WO 02/18404; published Aug. 21, 2001) filed by Roche,and PCT Publication Nos. WO 01/79246 (filed Apr. 13, 2001), WO 02/32920(filed Oct. 18, 2001) and WO 02/48165 by Pharmasset, Ltd. (thedisclosures of which are incorporated herein by reference in theirentireties)

PCT Publication No. WO 99/43691 to Emory University (incorporated hereinby reference in its entirety), entitled “2′-Fluoronucleosides” disclosesthe use of certain 2′-fluoronucleosides to treat HCV.

Eldrup et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16^(th)International Conference on Antiviral Research (Apr. 27, 2003, Savannah,Ga.)) described the structure activity relationship of 2′-modifiednucleosides for inhibition of HCV.

Bhat et al. (Oral Session V, Hepatitis C Virus, Flaviviridae, 2003 (OralSession V, Hepatitis C Virus, Flaviviridae; 16^(th) Internationalconference on Antiviral Research (Apr. 27, 2003, Savannah, Ga.); p A75)describes the synthesis and pharmacokinetic properties of nucleosideanalogues as possible inhibitors of HCV RNA replication. The authorsreport that 2′-modified nucleosides demonstrate potent inhibitoryactivity in cell-based replicon assays.

Olsen et al. (Oral Session V, Hepatitis C Virus, Flaviviridae; 16^(th)International Conference on Antiviral Research (Apr. 27, 2003, Savannah,Ga.) p A76) also described the effects of the 2′-modified nucleosides onHCV RNA replication.

(8) Nucleotide polymerase inhibitors and gliotoxin (Ferrari R. et al.Journal of Virology, 1999, 73, 1649-1654), and the natural productcerulenin (Lohmann V. et al. Virology, 1998, 249, 108-118);

(9) HCV NS3 helicase inhibitors, such as VP 50406 by ViroPhama andcompounds from Vertex. Other helicase inhibitors (Diana G. D. et al.,Compounds, compositions and methods for treatment of hepatitis C, U.S.Pat. No. 5,633,358 (incorporated herein by reference in its entirety);Diana G. D. et al., Piperidine derivatives, pharmaceutical compositionsthereof and their use in the treatment of hepatitis C, PCT WO 97/36554);

(10) Antisense phosphorothioate oligodeoxynucleotides (S-ODN)complementary to sequence stretches in the 5′ non-coding region (NCR) ofthe virus (Alt M. et al., Hepatology, 1995, 22, 707-717), or nucleotides326-348 comprising the 3′ end of the NCR and nucleotides 371-388 locatedin the core coding region of the HCV RNA (Alt M. et al., Archives ofVirology, 1997, 142, 589-599; Galderisi U. et al., Journal of CellularPhysiology, 199, 181, 251-257); such as ISIS14803 by Isis Pharm/Elan,antisense by Hybridon, antisense by AVI bioPharma,

(11) Inhibitors of IRES-dependent translation (Ikeda N et al., Agent forthe prevention and treatment of hepatitis C, Japanese Patent Pub.JP-08268890; Kai Y et al. Prevention and treatment of viral diseases,Japanese Patent Pub. JP-10101591); such as ISIS14803 by Isis Pharm/Elan,IRES inhibitor by Anadys, IRES inhibitors by Immusol, targeted RNAchemistry by PTC Therapeutics

(12) Ribozymes, such as nuclease-resistant ribozymes (Maccjak, D. J. etal., Hepatology 1999, 30, abstract 995) and those directed in U.S. Pat.No. 6,043,077 to Barber et al., and U.S. Pat. Nos. 5,869,253 and5,610,054 to Draper et al. (incorporated herein by reference in theirentireties) for example, HEPTAZYME by RPI

(13) siRNA directed against HCV genome

(14) HCV replication inhibitor of any other mechanisms such as byVP50406ViroPharama/Wyeth, inhibitors from Achillion, Arrow

(15) An inhibitor of other targets in the HCV life cycle including viralentry, assembly and maturation

(16) An immune modulating agent such as an IMPDH inhibitor, mycophenolicacid, a salt or a prodrug thereof sodium mycophenolate or mycophenolatemofetil, or Merimebodib (VX-497); thymosin alpha-1 (Zadaxin, bySciClone); or a S1P receptor agonist, e.g. FTY720 or analogue thereofoptionally phosphorylated.

(17) An anti-fibrotic agent, such as a N-phenyl-2-pyrimidine-aminederivative, imatinib (Gleevac), IP-501 by Indevus, and Interferon gamma1b from InterMune

(18) Therapeutic vaccine by Intercell, Epimmune/Genecor, Merix, Tripep(Chron-VacC), immunotherapy (Therapore) by Avant, T cell therapy byCellExSys, monoclonal antibody XTL-002 by STL, ANA 246 and ANA 246 BYAnadys,

(19) Other miscellaneous compounds including 1-amino-alkylcyclohexanes(U.S. Pat. No. 6,034,134 to Gold et al.), alkyl lipids (U.S. Pat. No.5,922,757 to Chojkier et al.), vitamin E and other anti-oxidants (U.S.Pat. No. 5,922,757 to Chojkier et al.), amantadine, bile acids (U.S.Pat. No. 5,846,99964 to Ozeki et al.), N-(phosphonoacetyl)-L-asparticacid, (U.S. Pat. No. 5,830,905 to Diana et al.), benzenedicarboxamides(U.S. Pat. No. 5,633,388 to Diane et al.), polyadenylic acid derivatives(U.S. Pat. No. 5,496,546 to Wang et al.), 2′3′-dideoxyinosine (U.S. Pat.No. 5,026,687 to Yarchoan et al.), benzimidazoles (U.S. Pat. No.5,891,874 to Colacino et al.), plant extracts (U.S. Pat. No. 5,837,257to Tsai et al., U.S. Pat. No. 5,725,859 to Omer et al., and U.S. Pat.No. 6,056,961) and piperidines (U.S. Pat. No. 5,830,905 to Diana etal.); the disclosures of which are incorporated herein by reference intheir entireties. Also, squalene, telbivudine,N-(phosphonoacetyl)-L-aspartic acid, benzenedicarboxamides, polyadenylicacid derivatives, glycosylation inhibitors, and nonspecificcytoprotective agents that block cell injury caused by the virusinfection.

(20) Any other compound currently in preclinical or clinical developmentfor the treatment of HCV, including Interleukin-10 (Schering-Plough),AMANTADINE (Symmetrel) by Endo Labs Solvay, caspase inhibitor IDN-6556by Idun Pharma, HCV/MF59 by Chiron, CIVACIR (Hepatitis C ImmuneGlobulin) by NABI, CEPLENE (histamine dichloride) by Maxim, IDN-6556 byIdun PHARM, T67, a beta-tubulin inhibitor, by Tularik, a therapeuticvaccine directed to E2 by Innogenetics, FK788 by Fujisawa Helathcare,IdB1016 (Siliphos, oral silybin-phosphatidyl choline phytosome), fusioninhibitor by Trimeris, Dication by Immtech, hemopurifier by AethlonMedical, Utah 231B by United Therapeutics.

(21) Purine nucleoside analog antagonists of TlR7 (toll-like receptors)developed by Anadys, e.g., Isotorabine (ANA245) and its prodrug(ANA975), which are described in European applications EP348446 andEP636372, International Publications WO03/045968, WO05/121162 andWO05/25583, and U.S. Pat. No. 6,973,322, each of which is incorporatedby reference.

(21) Non-nucleoside inhibitors developed by Genelabs and described inInternational Publications WO2004/108687, WO2005/12288, andWO2006/076529, each of which is incorporated by reference.

(22) Other co-agents (e.g., non-immunomodulatory or immunomodulatorycompounds) that may be used in combination with a compound of thisinvention include, but are not limited to, those specified in WO02/18369, which is incorporated herein by reference.

Methods of this invention may also involve administration of anothercomponent comprising an additional agent selected from animmunomodulatory agent; an antiviral agent; an inhibitor of HCVprotease; an inhibitor of another target in the HCV life cycle; a CYPinhibitor; or combinations thereof.

Accordingly, in another embodiment, this invention provides a methodcomprising administering a compound of the invention and anotheranti-viral agent, preferably an anti-HCV agent. Such anti-viral agentsinclude, but are not limited to, immunomodulatory agents, such as α, β,and δ interferons, pegylated derivatized interferon-a compounds, andthymosin; other anti-viral agents, such as ribavirin, amantadine, andtelbivudine; other inhibitors of hepatitis C proteases (NS2-NS3inhibitors and NS3-NS4A inhibitors); inhibitors of other targets in theHCV life cycle, including helicase, polymerase, and metalloproteaseinhibitors; inhibitors of internal ribosome entry; broad-spectrum viralinhibitors, such as IMPDH inhibitors (e.g., compounds of U.S. Pat. No.5,807,876, 6,498,178, 6,344,465, 6,054,472, WO 97/40028, WO 98/40381, WO00/56331, and mycophenolic acid and derivatives thereof, and including,but not limited to VX-497, VX-148, and/or VX-944); or combinations ofany of the above.

In accordance with the foregoing the present invention provides in a yetfurther aspect:

-   -   A pharmaceutical combination comprising a) a first agent which        is a compound of the invention, e.g. a compound of formula I or        any subformulae thereof, and b) a co-agent, e.g. a second drug        agent as defined above.    -   A method as defined above comprising co-administration, e.g.        concomitantly or in sequence, of a therapeutically effective        amount of a compound of the invention, e.g. a compound of        formula I or any subformulae thereof, and a co-agent, e.g. a        second drug agent as defined above.

The terms “co-administration” or “combined administration” or the likeas utilized herein are meant to encompass administration of the selectedtherapeutic agents to a single patient, and are intended to includetreatment regimens in which the agents are not necessarily administeredby the same route of administration or at the same time. Fixedcombinations are also within the scope of the present invention. Theadministration of a pharmaceutical combination of the invention resultsin a beneficial effect, e.g. a synergistic therapeutic effect, comparedto a monotherapy applying only one of its pharmaceutically activeingredients.

Each component of a combination according to this invention may beadministered separately, together, or in any combination thereof. Asrecognized by skilled practitioners, dosages of interferon are typicallymeasured in IU (e.g., about 4 million IU to about 12 million IU).

If an additional agent is selected from another CYP inhibitor, themethod would, therefore, employ two or more CYP inhibitors. Eachcomponent may be administered in one or more dosage forms. Each dosageform may be administered to the patient in any order.

The compound of the invention and any additional agent may be formulatedin separate dosage forms. Alternatively, to decrease the number ofdosage forms administered to a patient, the compound of the inventionand any additional agent may be formulated together in any combination.For example, the compound of the invention inhibitor may be formulatedin one dosage form and the additional agent may be formulated togetherin another dosage form. Any separate dosage forms may be administered atthe same time or different times.

Alternatively, a composition of this invention comprises an additionalagent as described herein. Each component may be present in individualcompositions, combination compositions, or in a single composition.

EXEMPLIFICATION OF THE INVENTION

The invention is further illustrated by the following examples, whichshould not be construed as further limiting. The assays used throughoutthe Examples are accepted. Demonstration of efficacy in these assays ispredictive of efficacy in subjects.

General Synthesis Methods

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

LIST OF ABBREVIATIONS

-   Ac acetyl-   ACN Acetonitrile-   AcOEt/EtOAc Ethyl acetate-   AcOH acetic acid-   aq aqueous-   Ar aryl-   Bn benzyl-   Bu butyl (nBu=n-butyl, tBu=tert-butyl)-   CDI Carbonyldiimidazole-   CH₃CN Acetonitrile-   DBU 1,8-Diazabicyclo[5.4.0]-undec-7-ene-   DCE 1,2-Dichloroethane-   DCM Dichloromethane-   DIPEA N-Ethyldiisopropylamine-   DMAP Dimethylaminopyridine-   DMF N,N′-Dimethylformamide-   DMSO Dimethylsulfoxide-   EI Electrospray ionisation-   Et₂O Diethylether-   Et₃N Triethylamine-   Ether Diethylether-   EtOH Ethanol-   FC Flash Chromatography-   h hour(s)-   HATU 0-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium    hexafluorophosphate-   HBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HCl Hydrochloric acid-   HOBt 1-Hydroxybenzotriazole-   HPLC High Performance Liquid Chromatography-   H₂O Water-   L liter(s)-   LC-MS Liquid Chromatography Mass Spectrometry-   Me methyl-   MeI Iodomethane-   MeOH Methanol-   mg milligram-   min minute(s)-   mL milliliter-   MS Mass Spectrometry-   Pd/C palladium on charcoal-   PG protecting group-   Ph phenyl-   Prep Preparative-   Rf ratio of fronts-   RP reverse phase-   Rt Retention time-   rt Room temperature-   SiO₂ Silica gel-   TBAF Tetrabutylammonium fluoride-   TEA Triethylamine-   TFA Trifluoroacetic acid-   THF Tetrahydrofurane-   TLC Thin Layer Chromatography

HPLC Methods: Method A: HPLC

Instrument: Agilent systemcolumn: waters symmetry C18, 3.5 μm, 2.1×50 mm, flow 0.6 ml/minsolvent: CH₃CN (0.1% CF₃CO₂H); H₂O (0.1% CF₃CO₂H)gradient: 0-3.5 min: 20-95% CH₃CN, 3.5-5 min: 95% CH₃CN, 5.5-5.55 min95% to 20% CH₃CN

Method B:

Agilent 1100 LC chromatographic system with Micromass ZMD MS detection.A binary gradient composed of A (water containing 5% acetonitrile and0.05% trifluoroacetic acid) and B (acetonitrile containing 0.045%trifluoroacetic acid) is used as a mobile phase on a Waters X Terra™C-18 column (30×3 mm, 2.5 μm particle size) as a stationary phase. Thefollowing elution profile is applied: a linear gradient of 3.5 minutesat a flow rate of 0.6 ml/min from 5% of B to 95% of B, followed by anisocratic elution of 0.5 minutes at a flow rate of 0.7 ml/min of 95% ofB, followed by an isocratic elution of 0.5 minutes at a flow rate of 0.8ml/min of 95% of B, followed by a linear gradient of 0.2 minutes at aflow rate of 0.8 ml/min from 95% of B to 5% of B, followed by aisocratic elution of 0.2 minutes at a flow rate of 0.7 ml/min of 5% ofB.

Method C: HPLC Instrument: Kontron, Kroma-System Column: Macherey-Nagel,Lichrosphere 100-5 RP 18 Solvent: CH₃CN (0.1% CF₃CO₂H); H₂O (0.1%CF₃CO₂H)

Gradient: 0-5 min: 10-100% CH₃CN; 5-7.5 min: 100% CH₃CN (Flow 1.5mL/min)

Example 1

Step 1-A:

To a solution of 1a (3.0 g, 7.84 mmol) in dichloromethane (20 mL) atroom temperature is added TFA (20 mL). The mixture is stirred for 3hours after which the solvent is evaporated in vacuo to give the desiredproduct (4.5 g). Found m/z ES+=283 and ES−=281.

Step 1-B:

A solution of 1c (2.18 g, 9.45 mmol) in anhydrous dichloromethane (57mL) and anhydrous DMF (57 mL) is stirred at 0° C. is added HATU (1.4 eq,5.0 g, 13.23 mmol). 1b (1.2 eq, 4.50 g, 11.34 mmol) is added in smallportions. Then, N-methylmorpholine (4.0 eq, 3.82 g, 37.8 mmol) is addeddropwise. The reaction mixture is gradually warmed to room temperatureand stirred for overnight. All the volatiles are removed under vacuumand the residue is dissolved in ethyl acetate. The organic layer iswashed with water, 1.0 N HCl aq. solution, aq. sat. NaHCO₃ solution, andbrine. The organic layer is dried over Na₂SO₄, filtered and concentratedin vacuo. The residue is chromatographed on silica gel (gradient:acetone/hexane; 2:8 to 1:1) to afford 1d (3.11 g). Found m/z ES+=496.

Step 1-C:

To a solution of 1d (3.1 g, 6.25 mmol) in dichloromethane (15 mL) atroom temperature is added TFA (15 mL). The mixture is stirred for 3hours after which the solvent is evaporated in vacuo to give 4.7 g of1e. Found m/z ES+=396.

Step 1-D:

A solution of Boc-L-2-cyclohexylglycine if (2.0 g, 7.79 mmol) inanhydrous dichloromethane (40 mL) and anhydrous DMF (40 mL) is stirredat 0° C. and treated with HATU (1.4 eq, 4.14 g, 10.90 mmol). 1e (1.2 eq,4.77 g, 9.35 mmol) is added in small portions. Then, N-methylmorpholine(4.0 eq, 3.15 g, 31.16 mmol) is added dropwise. The reaction mixture isgradually warmed to room temperature and stirred for overnight. All thevolatiles are removed under vacuum and the residue is dissolved inethylacetate. The organic layer is washed with water, aq. 1.0 N HClsolution, sat. aq. NaHCO₃ solution, and brine. The organic layer isdried over Na₂SO₄, filtered and concentrated in vacuo. The residue ischromatographed on silica gel (gradient: acetone/hexane; 2:8 to 1:1) toafford 3.0 g of 1g. Found m/z ES+=635.

Step 1-E:

A solution of 1g (3.0 g, 4.72 mmol) in 45 mL of a 1:1:1 mixture ofTHF/MeOH/water is added lithium hydroxide monohydrate (2 eq, 394 mg).The mixture is stirred for overnight. All the volatiles are evaporatedin a vacuo and to the residue is added dichloromethane (100 mL). The pHof the aqueous layer is adjusted to pH 5 with dropwise addition of aq.1.0 N HCl solution. The layers are separated and the aqueous layer isextracted with dichloromethane. The combined organic layers are dried(Na₂SO₄), filtered, and concentrated to afford 1.87 g of 1 h (1.87 g).Found m/z ES+=595 and ES−=593

Step 1-F:

A solution of 1i (2.80 g, 4.7 mmol) in anhydrous dichloromethane (24 mL)and anhydrous DMF (24 mL) is stirred at 0° C. and treated with HATU (1.4eq, 2.5 g, 6.58 mmol). The hydroxy ketoamide amine 1j (1.2 eq, 1.05 g,5.66 mmol) is added in small portions. Then, N-methylmorpholine (4.0 eq,1.90 g, 18.80 mmol) is added dropwise. The reaction mixture is graduallywarmed to room temperature and stirred for overnight. All the volatilesare removed under vacuum and the residue is dissolved in ethylacetate.The organic layer is washed with water, aq. 1.0 N HCl solution, sat. aq.NaHCO₃ solution, and brine. The organic layer is dried over Na₂SO₄,filtered and concentrated in vacuo. The residue is chromatographed onsilica gel (gradient: acetone/hexane; 2:8 to 1:1) to afford 3.0 g of 1k.Found m/z ES+=763 and ES−=761.

Step 1-G:

To a solution of 1k (4.0 g, 5.24 mmol) in dichloromethane (26 mL) atroom temperature is added TFA (26 mL). The mixture is stirred for 3hours after which the solvent is evaporated in vacuo and to the residueis added dichloromethane (100 mL). The pH is adjusted to 8 by dropwiseaddition of sat. aq. NaHCO₃ solution. The layers are separated. Theorganic layer is washed with brine, dried over Na₂SO₄, filtered andconcentrated to give 4.0 g of 1l (4.0 g). Found m/z ES+=663 and ES−=661.

Step 1-H:

To a solution of 1l (350 mg, 0.53 mmol) in dioxane (1.0 mL) at roomtemperature added 2-chlorobenzaxazole (122 mg, 0.79 mmol) and NaHCO₃ (89mg, 1.1 mmol). The mixtures are stirred at 65° C. for 6 hours. Themixture then is loaded directly to silica gel column and eluted withhexane/EtOH (from 95/5 to 85/15) to give 360 mg of 1m. Found m/z ES+=780and ES−=778.

Step 1-I:

To a solution of 1m (253 mg, 0.32 mmol) in CH₂Cl₂ (1.6 mL) at 0° C. isadded DIPEA (1.3 mmol, 168 mg) followed by a solution of pyridinesulfoxide (0.65 mmol, 103 mg) in DMSO (1.6 mL). The solution is stirredat 0° C. for 10 min. To the solution is added EtOAc and sat. aq. NH₄Clsolution. The two phases are separated and the aqueous layer isextracted with EtOAc. The organic layers are combined, washed withbrine, dried over Na₂SO₄ and concentrated. The residue is purified bysilica gel column chromatography (hexane/Acetone, 1/1) to give 245 mgof 1. Found m/z in ES+778, m/z in ES−=776.

Example 2

Step 2-A:

To a solution of the amine 1l (50 mg, 0.07 mmol) in dioxane (350 mL) atroom temperature is added 2-chloro-4,6-dimethoxytriazine (20 mg, 0.11mmol) and NaHCO₃ (13 mg, 0.16 mmol). The mixtures are stirred at 80° C.for 2 hours. The reaction mixture is concentrated in a vacuo and to theresidue is added ethyl acetate (30 mL). The organic layer is washed withaq. 1.0 N HCl solution, sat. aq. NaHCO₃ solution and brine. The organicsolution is then dried over sodium sulfate and concentrated.Purification using preparative TLC (eluent: Acetone/hexane, 1:1) afford48 mg of 2a. Found m/z ES+=802 and ES−=800.

Step 2-B:

A solution of 2a (48 mg, 0.06 mmol) in anhydrous dichloromethane (0.6mL) is treated with DMP (2.0 eq, 51 mg). The reaction mixture is stirredat room temperature for 30 minutes. The mixture is added aq. 1.0 Msodium thiosulfate solution (2 mL) and the resulted mixtures are stirredfor 5 minutes. Aq. sat. sodium bicarbonate solution (2 mL) is added andthe stirring is continued for another 10 minutes. The phases areseparated and the aqueous layer is extracted with dichloromethane. Thecombined organic layer are dried over sodium sulfate, filtered andconcentrated. The residue is chromatographed using silica gelpreparative TLC (Eluent: acetone/hexanes, 4:6) to afford 36 mg of 2.Found m/z ES+=800.

Example 3

Step 3-A:

To a solution of 3a (2.5 g, 7.0 mmol) in dichloromethane (6.0 mL) atroom temperature is added TFA (6 mL). The mixture is stirred for 3 hoursafter which the solvent is evaporated in vacuo to give 4.0 g of 3b.Found m/z ES+=257.

Step 3-B:

A solution of 1c (219 mg, 2.68 mmol) in anhydrous dichloromethane (13mL) and anhydrous DMF (13 mL) is stirred at 0° C. and treated with HATU(1.4 eq, 1.42 g, 3.75 mmol). 3b (1.0 eq, 0.99 g, 2.67 mmol) is added insmall portions. Then, N-methylmorpholine (4.0 eq, 1.08 g, 10.7 mmol) isadded dropwise. The reaction mixture is gradually warmed to roomtemperature and stirred for overnight. All the volatiles are removedunder vacuum and the residue is dissolved in ethylacetate. The organiclayer is washed with water, aq. 1.0 N HCl solution, sat. aq. sodiumbicarbonate solution, and brine. The organic layer is dried over Na₂SO₄,filtered and concentrated in vacuo. The residue is chromatographed onsilica gel (gradient: EtOAc/Hexane, 1:1)) to afford 1.3 g of 3c. Foundm/z ES+=470.

Step 3-C:

A solution of 3c (1.2 g, 2.55 mmol) in 12 mL of a 1:1:1 mixture ofTHF/MeOH/water is added lithium hydroxide monohydrate (2.0 eq, 214 mg).The mixture is stirred overnight. All the volatiles are evaporated in avacuo and to the residue is added dichloromethane. The pH of the aqueouslayer is adjusted to 5 with dropwise addition of aq. 1.0 N HCl solutionand layers are separated. The aqueous layer is extracted withdichloromethane. The combined organic layers are dried over sodiumsulfate, filtered, and concentrated to afford 822 mg of 3d. Found m/zES+=456 and ES−=454.

Step 3-D:

A solution of 3d (822 mg, 1.8 mmol) in anhydrous dichloromethane (4.5mL) and anhydrous DMF (4.5 mL) is stirred at 0° C. and treated with HATU(1.4 eq, 962 mg, 2.53 mmol). 1j (1.0 eq, 335 mg, 1.8 mmol) is added insmall portions. Then, N-methylmorpholine (4.0 eq, 731 mg, 7.23 mmol) isadded dropwise. The reaction mixture is gradually warmed to roomtemperature and stirred overnight. All the volatiles are removed undervacuum and the residue is dissolved in ethylacetate. The organic layeris washed with water, aq. 1.0 N HCl solution, sat. aq. sodiumbicarbonate solution, and brine. The organic layer is dried over Na₂SO₄,filtered and concentrated in vacuo. The residue is chromatographed onsilica gel (gradient: acetone/Hexanes, 3:7) to afford 800 mg of 3e.Found m/z ES+=624.

Step 3-E:

To a solution of 3e (800 mg, 1.28 mmol) in dichloromethane (3.5 mL) atroom temperature is added trifluoroacetic acid (3.5 mL). The mixture isstirred for 3 hours after which the solvent is evaporated in vacuo andto the residue is added dichloromethane. The pH is adjusted to 8 bydropwise addition of sat. aq. sodium bicarbonate solution. The layersare separated. The organic layer is washed with brine, dried overNa₂SO₄, and concentrated to give 3f. Found m/z ES+=524.

Step 3-F:

To mixtures of H-cyclohexyl-gly-OMe.HCl (2.07 g, 10 mmol) in CH₂Cl₂ (100mL) and saturated aqueous NaHCO₃ solution (100 mL) at room temperatureadded CSCl₂ (0.804 mL, 10 mmol). The mixture is stirred at roomtemperature for 30 minutes. The two phases are separated and the aqueouslayer is extracted with CH₂Cl₂. The organic layers are combined, driedover Na₂SO₄ and concentrated to give 2.1 g of 3h, which is continued tothe next step with no further purification.

To a solution of 2-amino-2-methyl-1-propanol (178 mg, 2.0 mmol) in THF(2.0 mL) added 3h (426 mg, 2.0 mmol). The solution is stirred at roomtemperature for 12 hours after which the solvent is evaporated. Theresidue is purified by silica gel column chromatography (hexane/EtOAc,2/1) to give 438 mg of 31. Found m/z in ES+=303, m/z in ES−=301.

To a solution of 31 (60 mg, 0.2 mmol) in CH₃CN (2.0 mL) at 0° C. isadded a solution of 2-chloro-3-ethylbenzoxazolium tetrafluoroborate (81mg, 0.3 mmol, 1.5 equiv) in CH₃CN (1.0 mL). The solution is stirred atroom temperature for 30 minutes after which TEA (0.139 mL, 1.0 mmol, 5.0equiv) is added and the solution is stirred at room temperature foranother 30 minutes. The solvent is then evaporated and the residue ispurified by silica gel column chromatography (hexane/EtOAc, 4/1 to 0/1)to give 40 mg of 3j. Found m/z in ES+=269.

To a solution of 3j (57 mg, 0.2 mmol) in CH₂Cl₂ (0.2 mL) added TEA(0.056 mL, 0.4 mmol, 2.0 equiv), 2-nitrobenzenesulfonyl chloride (66 mg,0.3 mmol, 1.5 equiv) and DMAP (10 mg). The solution is stirred at roomtemperature for 4 hours. The mixtures are then directly loaded to silicagel column and flushed with hexane/EtOAc (9/1 to 1/1) to give 67 mg of3k. Found m/z in ES+=454.

To a solution of 3k (40 mg) in THF (0.3 mL), MeOH (0.3 mL) at 0° C. isadded a solution of LiOH.H₂O (12 mg) in water (0.3 mL). The solution isstirred at room temperature for 8 hours, after which aq. 1.0 N HClsolution is added. The mixtures are extracted with CH₂Cl₂. The combinedorganic layer is dried over Na₂SO₄ and concentrated to give 3g. Foundm/z in ES+=440, m/z in ES−=438.

Step 3-G:

A solution of the acid 3g (47 mg, 0.11 mmol) in anhydrousdichloromethane (0.5 mL) and anhydrous DMF (0.5 mL) is stirred at 0° C.and treated with HATU (1.4 eq, 57 mg, 0.15 mmol). To the solution 3f(1.2 eq, 62 mg, 0.12 mmol) is added in small portions. Then,N-methylmorpholine (4.0 eq, 0.047 mL, 0.43 mmol) is added dropwise. Thereaction mixture is gradually warmed to room temperature and stirred forovernight. All the volatiles are removed under vacuum and the residue isdissolved in ethylacetate. The organic layer is washed with water, aq.1.0 N HCl solution, aq. sat. sodium bicarbonate solution, and brine. Theorganic layer is dried over Na₂SO₄, filtered and concentrated in vacuo.The residue is chromatographed on silica gel (eluent: acetone/hexane;1:1) to afford the desired product 3m. Found m/z ES+=945.

Step 3-H:

To a solution of 3m (50 mg, 0.05 mmol) in DMF (0.5 mL) is addedmercaptoacetic acid (19 mg, 0.21 mmol) and monohydrate lithium hydroxide(18 mg, 0.42 mmol) at room temperature. The reaction mixture is stirredfor 3 hours after which sat. aq. sodium bicarbonate solution is added.The phases are separated and the aqueous layer is extracted with ethylacetate. The combined organic layers are washed with brine, dried oversodium sulfate, and concentrated to give the desired product 3n. Foundm/z ES+=760.

Step 3-I:

To a solution of 3n (35 mg, 0.05 mmol) in anhydrous dichloromethane (0.5mL) is added Dess-Martin periodinane (2.0 eq, 39 mg) and the mixturesare stirred at room temperature for 30 minutes. To the reaction mixturesis added aq. 1.0 M sodium thiosulfate solution (1 mL) and stirred for 5minutes. Aq. sat. sodium bicarbonate solution (2 mL) is added and thestirring is continued for another 10 minutes. The mixtures are extractedwith dichloromethane. The combined organic layers are dried over sodiumsulfate, and concentrated. The residue is purified using silica gelpreparative TLC plate (Eluent: acetone/hexanes, 1:1) to afford thedesired product 3. Found m/z ES+=758

Example 4

Step 4-A:

To a solution of H-cyclohexyl-gly-OMe.HCl in water (1.0 mL) and dioxane(1.0 mL) added NaOH (60 mg, 1.5 mmol, 3.0 equiv) and3-chloro-benzoisothiazole 1,1-dioxide (220 mg, 1.0 mmol, 1.0 equiv). Thesolution is stirred at room temperature for 1 hour, after which the pHof the solution is adjusted to 5 by addition of 1.0 N HCl aqueoussolution. The two phases are separated and the aqueous phase isextracted with CH₂Cl₂. The organic layers are combined, washed withbrine, dried over Na₂SO₄, concentrated. The residue is purified bysilica gel column chromatography (hexane/EtOAc, 1/1) to give 150 mg of4b. Found m/z in ES+=337, m/z in ES−=335.

To a solution of methyl ester 4b (100 mg) in THF (0.3 mL) and MeOH (0.3mL) at 0° C. is added a solution of LiOH.H₂O (25 mg) in water (0.3 mL).The solution is stirred at room temperature for 3 hours. The pH of thesolution is then adjusted to 6 by addition of 1.0 N HCl aqueoussolution. CH₂Cl₂ is then added and the two phases are separated. Theaqueous layer is extracted with CH₂Cl₂. The organic layers are combined,washed with brine, dried over Na₂SO₄ and concentrated to give 75 mg of4a. Found m/z in ES+=323, m/z in ES−=321.

Step 4-B:

A solution of 4a (74 mg, 0.23 mmol) in anhydrous dichloromethane (1.0mL) and anhydrous DMF (1.0 mL) is stirred at 0° C. and treated with HATU(1.4 eq, 105 mg, 0.27 mmol). To this solution is added 3f (1 eq, 120 mg,0.23 mmol) is added in small portions. Then, N-methylmorpholine (4.0 eq,0.101 mL, 0.92 mmol) is added dropwise. The reaction mixture isgradually warmed to room temperature and stirred for overnight. All thevolatiles are removed under vacuum and the residue is dissolved inethylacetate. The organic layer is washed with water, aq. 1.0 N HClsolution, aqueous saturated sodium bicarbonate solution, and brine. Theorganic layer is dried over Na₂SO₄ and concentrated in vacuo. Theresidue is chromatographed on silica gel (eluent: acetone/hexane; 1:1)to afford the desired product 4c. Found m/z ES+=828.

Step 4-C:

A solution of 4c (41 mg, 0.05 mmol) in anhydrous dichloromethane (3 mL)is treated with Dess-Martin periodinane (3.0 eq, 63 mg) and the reactionmixtures are stirred at room temperature for 30 minutes. To the mixtureis added aqueous 1.0 M sodium thiosulfate solution (2 mL) and stirredfor 5 minutes. Aqueous saturated sodium bicarbonate solution (2 mL) isadded and stirring is continued for another 10 minutes. The mixture isextracted with dichloromethane. The combined organic layers are driedover sodium sulfate, filtered and concentrated. The residue is purifiedby silica gel column chromatography (acetone/hexanes, 1:1) to afford thedesired product 4. Found m/z ES+=826 and m/z ES−=824.

Example 5

Step 5-A:

To a solution of 5a (5.0 g, 29.56 mmol) in ethanol (60 mL) is added Pd/C(20%, 1.0 g). The reaction mixture is then stirred under 1.0 atm. of H₂balloon for 12 h. The reaction mixture is then filtered through celite545 and the filtrate is concentrated to give 3.6 g of 5b.

Step 5-B:

Mixtures of 5b (1.2 g, 8.62 mmol), potassium hydroxide (581 mg, 10.34mmol) and carbon disulfide (10 mL, 173 mmol) in ethanol (17 mL) areheated to refluxed overnight. The solvent is then evaporated. To theresidue aqueous 1.0 N HCl solution (10 mL) and ethylacetate (100 mL) areadded. The phases are separated. The organic layer is washed with water,brine, dried over sodium sulfate and concentrated to give 1.2 g of 5c.

Step 5-C:

To 5c (1.0 g, 5.5 mmol) and thionyl chloride (6 mL, 66 mmol) is addedtwo drops of DMF and the resulted mixtures are heated at 70° C. for 30minutes. The solution is then cooled to room temperature and dilutedwith dichloromethane. The solvent is then evaporated. To the residue isadded another 10 mL of dichloromethane and the solution is concentrated.The residue is dissolved in hot hexanes and then filtered. The filtrateis concentrated to give 1.0 g of 5d.

Step 5-D:

To a solution of 1l (75 mg, 0.11 mmol) in dioxane (0.4 mL) at roomtemperature is added 5d (31 mg, 0.17 mmol) and sodium bicarbonate (19mg, 0.23 mmol). The mixtures are stirred at 65° C. for 12 hours. Themixtures are loaded directly to silica gel column and eluted withhexane/EtOH (from 95/5 to 85/15) to give 5e. Found m/z ES+=810 andES−=808.

Step 5-E:

A solution of 5e (62 mg, 0.08 mmol) in anhydrous dichloromethane (0.80mL) is added Dess-Martin periodinane (2.0 eq, 65 mg). The reactionmixture is stirred at room temperature for 30 minutes. To the mixture isadded aqueous 1.0 M sodium thiosulfate solution (2 mL) and stirred for 5minutes. Aqueous saturated sodium bicarbonate solution (2 mL) is addedand stirring is continued for another 10 minutes. The mixture isextracted with dichloromethane. The combined organic layers are driedover sodium sulfate, filtered and concentrated. The residue is purifiedusing silica gel preparative TLC (gradient: acetone/hexanes, 3:7 to 1:1)to afford the desired product 5. Found m/z ES+=808 and ES−=806.

Example 6

A solution of 1l (100 mg, 0.15 mmol, 1.0 equiv) and 6a (27 mg, 0.15mmol, 1.0 equiv) in EtOH (0.5 mL) is stirred at room temperature for 1hour. Found m/z for 6b ES+=843, m/z in ES−=841.

To the above solution added SnCl₂ (142 mg, 0.75 mmol) and the mixturesare heated at 70° C. for 30 minutes. The solution is then cooled at 0°C. Ice is added followed by saturated aqueous NaHCO₃ and EtOAc. Thephases are separated and the aqueous layer is extracted with EtOAc. Theorganic layers are combined, washed with brine, dried over Na₂SO₄,concentrated to give crude product 6c, which is continued to the nextstep without further purification. Found m/z in ES+=813, m/z in ES−=811.

To a solution of 6c (120 mg, 0.15 mmol) in toluene (0.6 mL) added HgO(64.8 mg, 0.3 mmol, 2.0 equiv) and sulfur (4.8 mg, 0.15 mmol, 1.0 equiv)and the mixtures are stirred at 90° C. for 1 hour. The mixtures arefiltered, washed with CH₂Cl₂ and the solution is concentrated. Theresidue is purified by silica gel column chromatography(hexane/EtOH=4/1) to give desired product 6d (54 mg). Found m/z inES+=779.

To a solution of alcohol 6d (54 mg, 0.069 mmol) in CH₂Cl₂ (1.0 mL) at 0°C. is added DMP (58.7 mg, 0.138 mmol, 2.0 equiv). The solution isstirred at room temperature for 4 hours. The solution is then addedsaturated aqueous NaHCO₃ and 1.0 M Na₂S₂O₃ aqueous solution. The phasesare separated and the aqueous layer is extracted with CH₂Cl₂. Theorganic layers combined, washed with brine, dried over Na₂SO₄ andconcentrated. The residue is purified by silica gel columnchromatography (hexane/acetone 1/1) to give product

6. Found m/z in ES+=777.

Example 7

To a solution of isopropyldiphenylsulfonium tetrafluoroborate (ref.Matsuyama, H. et al. J. Org. Chem. 2000, 65, 4796.) (13.4 g, 42.5 mmol,1.7 equiv) in THF at −78° C. is added t-BuLi (22.0 mL, 37.5 mmol, 1.70 Min pentane, 1.5 equiv) and the solution is stirred at this temperaturefor 30 minutes. To the solution is then added a solution of 7a (5.0 g,25 mmol, 1.0 equiv) in THF (20 mL). The solution is stirred at −78° C.for 1 hour. The reaction is quenched by addition of saturated aqueousNaHCO₃. The solution is warmed to room temperature and diluted withEtOAc. The two phases are separated and the organic layer is washed withbrine, dried over Na₂SO₄ and concentrated. The residue is purified bysilica gel column chromatography (hexane/EtOAc, 9/1 to 3/1) to give 5.1g of 7b. 7b is converted to the amino alcohol 7c according to thereference: J. Org. Chem. 1999, 64, 330.

To a solution of Boc-L-cyclohexyl-gly-OH (2.57 g, 10 mmol, 1.0 equiv) inCH₃CN (60.0 mL) at 0° C. is added HATU (3.878 g, 10.2 mmol, 1.02 equiv),HOAT (1.38 g, 10.2 mmol, 1.02 equiv) followed by 7c (1.39 g, 10 mmol,1.0 equiv) and DIPEA (6.95 mL, 40 mmol, 4.0 equiv). The solution isstirred at room temperature for 12 hours, after which the solvent isevaporated. The residue is partitioned between EtOAc and water. Thephases are separated and the organic layer is washed with saturatedaqueous NaHCO₃, brine, dried over Na₂SO₄ and concentrated. The residueis purified by silica gel column chromatography (hexane/EtOAc, 1/1) togive product 7d (3.43 g).

To a solution of 7d (2.4 g, 6.5 mmol) in acetone (40.0 mL) at −5° C. isadded a solution of Jones's reagent (3.0 M, 10.7 mL). The mixture iswarmed to 0° C. and stirred at this temperature for 2 hours. Thereaction is then quenched by slow addition of i-PrOH (10 mL) and themixture is then filtered. The phases are separated and the aqueous layeris extracted with EtOAc. The organic layers are combined, washed withbrine, dried (Na₂SO₄) and concentrated to give desired product 7e 2.35g. The material is continued to the next step with no furtherpurification. Found m/z in ES+=395, m/z in ES−=393.

To a solution of 7e (1.0 g, 2.5 mmol) in DMF (5.0 mL) and CH₂Cl₂ (5.0mL) at 0° C. is added HATU (1.05 g, 2.75 mmol, 1.1 equiv), 7f (0.53 g,2.5 mmol, 1.0 equiv) and N-methyl-morpholine (0.825 mL, 7.5 mmol, 3.0equiv). The solution is stirred at 0° C. for 30 minutes then at roomtemperature for 6 hours. To the reaction mixture is added saturatedaqueous NaHCO₃ solution and EtOAc. The two phases are separated and theaqueous layer is extracted with EtOAc. The organic layers are combined,washed with brine, dried over Na₂SO₄ and concentrated. The crudematerial is purified by silica gel column chromatography (hexane/EtOH,9/1) to give product 7g (950 mg). Found m/z in ES+=549.

To a solution of 7g (110 mg) in CH₂Cl₂ (2.0 mL) added TFA (2.0 mL) andthe solution is stirred at room temperature for 1 hour. The solvent isthen evaporated. The residue is added saturated aqueous NaHCO₃ solutionand EtOAc. The two phases are separated and the aqueous layer isextracted with EtOAc. The organic layers are combined, dried over Na₂SO₄and concentrated to give desired product 7h (67 mg). Found m/z inES+=449.

To a solution of 7h (150 mg, 0.33 mmol) in dioxane (1.0 mL) at roomtemperature added 2-chlorobenzaxazole (76 mg, 0.50 mmol, 1.5 equiv) andNaHCO₃ (84 mg, 1.0 mmol, 3.0 equiv). The mixture is stirred at 60° C.for 6 hours. The mixture are then loaded directly to silica gel columnand eluted with hexane/acetone (2/1) to give desired product 7l (145mg). Found m/z in ES+=566, m/z in ES−=564.

To a solution of 7i (120 mg, 0.21 mmol) in CH₂Cl₂ (2.0 mL) at 0° C. isadded DIPEA (0.148 mL, 0.848 mmol, 4.0 equiv) followed by a solution ofPy.SO₃ (67.6 mg, 0.424 mmol, 2.0 equiv) in DMSO (2.0 mL). The solutionis then stirred at 0° C. for 10 minutes. To the solution is added EtOAcand saturated aqueous NaHCO₃ solution. The two phases are separated andthe aqueous layer is extracted with EtOAc. The organic layers arecombined, washed with brine, dried over Na₂SO₄ and concentrated. Theresidue is purified by silica gel column chromatography (hexane/Acetone,1/1) to give product 7j (108 mg). Found m/z in ES+=564, m/z in ES−=562.

Example 8

Step 8-A:

To a solution of DIPA (12.4 mL, 88.6 mmol, 1.2 equiv) in THF (400 mL) at−30° C. is added n-BuLi (50 mL, 1.60 M in hexane, 81.0 mmol, 1.10equiv). The solution is stirred at this temperature for 30 minutes. Asolution of 8a (8a is prepared according to J. Org. Chem. 1986, 51,3140.) (15.0 g, 73.8 mmol, 1.0 equiv) is subsequently added to thesolution, which is then stirred at −30° C. for 30 minutes. A stream ofHCHO (22.0 g, 738 mmol, 10 equiv) and N₂ gas is bubbled through thissolution over 10 minutes. The reaction mixture is warmed up to 0° C.over 30 minutes and quenched by addition of 2.0 N HCl aqueous solutionuntil pH=3. EtOAc is added and the phases are separated. The aqueouslayer is extracted with EtOAc three times. The combined organic layer iswashed with brine, dried over Na₂SO₄ and concentrated to give 8b, whichis used in the next step without purification.

Step 8-B:

To a solution of 8b in CH₂Cl₂ (200 mL) at 0° C. is added TEA (30.9 mL,222 mmol, 3.0 equiv), DMAP (902 mg, 7.4 mmol, 0.1 equiv) and MsCl (11.5mL, 148 mmol, 2.0 equiv). The reaction temperature is maintained <5° C.The solution is stirred at room temperature for 2 hours. Then saturatedaqueous NH₄Cl solution is added followed by 1/1 mixture of EtOAc/TBME.The phases are separated and the aqueous layer is extracted with EtOAc.The organic layers are combined, washed with brine, dried with Na₂SO₄and concentrated to afford 8c, which is continued to the next step withno purification.

Step 8-C:

The residue 8c from previous step is dissolved in CH₂Cl₂/toluene (20mL/20 mL). At 0° C., 15 mL of DBU is added. The internal temperature iskept below 20° C. The solution is stirred at room temperature for 2hours. The mixture is loaded directly to silica gel column and flushedwith hexane/EtOAc (2/1 to 1/1) to give product 5 (7.4 g). The product 8dis carried onto the next step immediately.

Found m/z in ES+=216; LC-MS (method A) t_(R)=0.86 min

Step 8-D:

To a solution of isopropyl triphenyl phosphine iodide (10.4 g, 24.1mmol, 1.4 equiv) in THF (70 mL) at −30° C. is added n-BuLi (1.60 M, 13.9mL, 22.4 mmol). The solution is stirred at 0° C. for 30 minutes, thencooled at −30° C. A solution of 8d (3.7 g, 17.2 mmol, 1.0 equiv) isadded to above solution. The resulted reaction mixture are warmed up toroom temperature over 1 hour and stirred at room temperature for 3 hour.The reaction is quenched by addition of saturated aqueous NaHCO₃solution. After diluted with EtOAc, the mixture is filtered. The twophases are separated and the aqueous layer is extracted with EtOAc. Theorganic layers are combined, washed with brine, dried over Na₂SO₄ andconcentrated. The residue is purified by silica gel columnchromatography (hexane/EtOAc 3/1 to 2/1) to give product 8e (1.1 g), and8f (2.3 g).

TLC, Rf (EtOAc/heptane 1:2)=0.53 (8e) and 0.46 (8f)

Step 8-E: Procedure for the Synthesis of 8j.

To a solution of 8f (5.0 g, 19.5 mmol) in THF (75 mL) at 0° C. is addedLiAlH₄ (2.2 g, 58.4 mmol, 3. equiv). The solution is heated to refluxfor 5 hours. After cooled to 0° C., the reaction solution is slowlyadded 5.0 mL of saturated aqueous Na₂SO₄ solution. The mixtures arediluted with EtOAc and stirred at room temperature for 30 minutes. Themixture is filtered and the solution is concentrated to give product 8h(−5.0 g).

HPLC (method B) t_(R)=2.64 min

TLC, Rf (CH₂Cl₂/MeOH 9:1)=0.48

MS (method C): 246 [M+H]

Step 8-F:

To a solution of 8h (3.0 g) in EtOAc/HOAc (40 mL/40 mL) at roomtemperature added Pd (10% on carbon) 2.0 g. The mixture is placed under40 psi H₂ parr shaker for 3 hours. The mixture is diluted with CH₂Cl₂and filtered. The solution is concentrated. Most of the HOAc is removedunder vacuum at 30 Torr, 40° C. The solution is basified to pH=13 with6.0 M aqueous NaOH solution. After diluted with CH₂Cl₂, the solution isfiltered. The two phases are separated and the aqueous layer isextracted with CH₂Cl₂. The organic layers are combined, washed withbrine, dried over Na₂SO₄, K₂CO₃, concentrated to give product 8j (1.8g).

TLC, R_(f) (CH₂Cl₂/MeOH 4:1)=0.29

MS (method C): 156 [M+H]

Compound 8i is prepared from 8g by analogous procedure used to convert8h to 8j.

Example 9

Step 9-A:

To a solution of DIPA (6.6 mL, 47.3 mmol, 1.2 equiv) in THF (200 mL) at−30° C. is added n-BuLi (27 mL, 1.60 M in hexane, 43.3 mmol, 1.10equiv). The solution is stirred at this temperature for 30 minutes. Thena solution of 8a (15.0 g, 73.8 mmol, 1.0 equiv), which is preparedaccording to J. Org. Chem. 1986, 51, 3140, is added to the reaction andthe solution is stirred at −78° C. for 30 minutes. To this solution isadded propanal (3.4 mL, 47.3 mmol, 1.2 equiv). After 1.5 hours, thereaction is quenched by addition of 4.0 N HCl aqueous solution untilpH=3. EtOAc is added and the phases are separated. The aqueous layer isextracted with EtOAc three times. The combined organic layer is washedwith brine, dried over Na₂SO₄ and concentrated. The residue is continuedto the next step with no further purification.

The product obtained from the previous step are dissolved in CH₂Cl₂ (40mL). To this solution at 0° C. is added TEA (10.9 mL, 78.8 mmol, 2.0equiv), DMAP (950 mg, 7.8 mmol, 0.2 equiv), followed by SLOW addition ofMsCl (4.6 mL, 59.1 mmol, 1.5 equiv). The reaction temperature ismaintained <5° C. The solution is stirred at room temperature for 2hours. Then saturated aqueous NH₄Cl solution is added followed by 1/1mixture of EtOAc/diethyl ether. The phases are separated and the aqueouslayer is extracted with EtOAc. The organic layers are combined, washedwith brine, dried with Na₂SO₄ and concentrated.

The residue from the previous step is dissolved in CH₂Cl₂ (30.0 mL). At0° C., 10 mL of DBU is added. The internal temperature is kept below 20°C. The solution is stirred at room temperature for 2 hours. The mixtureis loaded directly to silica gel column and flushed with hexane/EtOAc(2/1 to 1/1) to give products 9a (3.7 g) and 9b (4.2 g).

Step 9-B:

To a solution of 9a (1.7 g) in CHCl₃ (10 mL) at room temperature isadded aq. NaOH solution (12g, 1/1 mixtures) and benzyltriethylammoniumchloride (227 mg). The solution is stirred at room temperature for 12hours. Then the mixtures are partitioned between EtOAc and water. Theaqueous layer is separated and extracted with EtOAc. The organic layersare combined, washed with brine, dried over Na₂SO₄ and concentrated. Theresidue is purified by flash chromatography (9/1 heptane/EtOAc to 2/2heptane/EtOAc) to give product 9c and 9d.

Step 9-C:

To a solution of 9c (1.8 g, 5.5 mmol) in THF (30 mL) at 0° C. is slowlyadded LiAlH₄ (1.05 g, 27.6 mmol, 5.0 equiv). The solution is heated toreflux for 5 hours. After cooled to 0° C., the reaction solution isslowly added 2.5 mL of saturated aqueous Na₂SO₄ solution. The mixture isdiluted with EtOAc and stirred at room temperature for 30 minutes. Themixture is filtered and the solution is concentrated. The residue isused in the subsequent step without further purification.

The isolated material (1.0 g) from previous step is dissolved in 18 mLof THF and 5.0 g of t-BuOH. To the solution is added small sodium pieces(1.6 g, 71 mmol, 20 equiv). The mixture is heated to reflux for about 6hours. The sodium is taken out and quenched with EtOH. The solution isadded 5 mL of EtOH and stirred at room temperature until there is nosodium left. The mixture is added ice and diluted with EtOAc. The twophases are separated and the aqueous layer is extracted with EtOAc. Theorganic layers are combined and washed with brine, dried over Na₂SO₄ andconcentrated. The residue is purified by silica gel chromatography(heptane/EtOAc, 1/1) to give product 9e.

Step 9-D:

Palladium on carbon (10%; 300 mg) is added to a solution of 9e (500 mg)in EtOAc/HOAc (4.0 mL/3.0 mL) at room temperature. The mixture is placedunder 40 PSI H₂ (2.7×10⁵ Pa) in a Parr shaker for 3 hours. The mixtureis diluted with CH₂Cl₂ and filtered. The solution is concentrated. Mostof the HOAc is removed under vacuum at 30 Ton, 40° C. The solution isbasified to pH=13 with 6.0 M aqueous NaOH solution. After diluted withCH₂Cl₂, the solution is filtered. The two phases are separated and theaqueous layer is extracted with CH₂Cl₂. The organic layers are combined,washed with brine, dried over Na₂SO₄, K₂CO₃ and concentrated to giveproduct 9f. Compound 9g is prepared from 9b by analogous procedure usedto convert 9a to 9f.

Example 10

Scheme:

Step 10-A:

To a solution of DIPA (7.66 mL, 54.2 mmol, 1.1 equiv) in THF (100 mL) at0° C. is added n-BuLi (33.9 mL, 1.60 M in hexane 54.2 mmol, 1.10 equiv).The solution is stirred at this temperature for 30 minutes. A solutionof 8a (10.0 g, 49.3 mmol, 1.0 equiv) in THF (10.0 mL) is added to themixture and the solution is stirred at −78° C. for 60 minutes.

Cyclobutanone (3.76 g, 49.3 mmol, 1.0 equiv) and Et₂O.BF₃ (6.19 mL, 49.3mmol) is added to this solution. The reaction mixture is stirred foranother 2.5 hours and quenched by addition of saturated NH₄Cl (100 mL).EtOAc is added and the phases are separated. The aqueous layer isextracted with EtOAc. The combined organic layers are washed with brine,dried over Na₂SO₄ and concentrated to afford 10a, which is used in thesubsequent reaction without further purification. Found m/z in ES+=274.

Step 10-B:

The residue containing compound 10a from the previous step is dissolvedin CH₂Cl₂ (150 mL). Triethyl amine (TEA) (52.1 mL, 374 mmol) and MsCl(2.89 mL, 37.4 mmol) are added to the solution, which is stirred atreflux for 8 hours. The reaction mixture is then added water and thephases are separated. The aqueous layer is extracted with CH₂Cl₂. Theorganic layers are combined, washed with brine, dried with Na₂SO₄ andconcentrated to afford compound 10b. Found m/z in ES+=256.

Step 10-C:

To a solution of 10b (2.54 g, 10 mmol) in CHBr₃ (25 mL) is addedsequentially benzyl triethyl ammonium chloride (0.46 g, 2 mmol) and 50%NaOH/water (20 mL) at 0° C. The mixture is stirred at room temperaturefor 2 hours and then at 50° C. for 1 hour. The reaction mixture isdiluted with water and the aqueous phase is extracted at least twicewith CH₂Cl₂. The combined organic phases are washed by brine, dried overNa₂SO₄ and concentrated. The isomers 10c and 10d are separated by flashchromatography (Heptane/EtOAc, 4:1). The upper spot by thin layerchromatography is 10c (1.43 g). Found m/z in ES+=428.

Step 10-D:

MeLi (16.5 mL 1.6 M solution, 26.4 mmol) is added dropwise to asuspension of CuI in THF at 0° C. to form a clear solution which ismaintained at 0° C. for 10 minutes. A solution of 10c (800 mg) in THF(8.0 mL) is added dropwise to the mixture at a temperature of −50° C. orless. After complete addition, the reaction mixture is warmed to 0° C.over 20 minutes. The solution is then cooled at −78° C. To this solutionis added methyl iodide (10 mL). The reaction mixture is warmed to roomtemperature over 1 hour. Saturated aqueous NH₄Cl solution (50 mL) is theadded to the solution and the solution is stirred for 10 minutes. Theprecipitate removed by filtration. The filtrate is partitioned betweenEtOAc and water. The two phases are separated and the aqueous phase isextracted with EtOAc. The combined organic phases are dried over Na₂SO₄,concentrated. The residue is purified by silica gel columnchromatography (heptane/EtOAc, 4/1) to give 10e (380 mg). Found m/zES+=298.

Step 10-E:

Compound 10e is converted to amino alcohol 10 according to the proceduredescribed for transforming compound 8f to 8j.

Example 11

Step 11-A:

To a solution of Boc-L-t-butyl-gly-OH (907 mg, 3.92 mmol, 1.0 equiv) andamino alcohol 8i (600 mg, 3.92 mmol, 1.0 equiv) in CH₂Cl₂ (20.0 mL) at0° C. is added HATU (1.638 g, 4.31 mmol, 1.1 equiv) followed by andDIPEA (2.0 mL, 11.76 mmol, 3.0 equiv). The solution is stirred at −20°C. for 24 hours, 0° C. for 3 hour and room temperature for 1 hour. Thereaction mixture is diluted with EtOAc and washed with 10% citric acid.The phases are separated and the aqueous layer is extracted with EtOAc.The organic layers are combined and washed with saturated aqueousHaHCO₃, brine, dried over Na₂SO₄ and concentrated. The residue ispurified by silica gel column chromatography (hexane/EtOAc, 1/1) to giveproduct 11a (1.2 g).

To a solution of alcohol 11a (1.2 g) in acetone (20.0 mL) at −5° C. isadded a solution of Jones' reagent (3.0 M, 5.0 mL). The mixture iswarmed to 0° C. and stirred at this temperature for 2 hours. Thereaction is then quenched by slow addition of i-PrOH (5.0 mL) and themixture is then diluted with EtOAc. The phases are separated and theaqueous layer is extracted with EtOAc. The organic layers are combined,washed with brine, dried (Na₂SO₄) and concentrated to give 11b (1.16 g).

Step 11-B:

To a solution of 11b (768 mg, 2.0 mmol) in DMF (2.0 mL) and CH₂Cl₂ (2.0mL) at 0° C. is added HATU (836 mg, 2.2 mmol, 1.1 equiv), 7f (417 mg,2.0 mmol, 1.0 equiv) and N-methyl-morpholine (0.658 mL, 6.0 mmol, 3.0equiv). The solution is stirred at room temperature for 3 hours. Thereaction mixture is added saturated aqueous NaHCO₃ solution andEtOAc/diethyl ether 1/1. The two phases are separated and the aqueouslayer is extracted with EtOAc. The organic layers are combined, washedwith 1.0 N HCl, brine, dried over Na₂SO₄ and concentrated. The crudematerial is purified by silica gel column chromatography (hexane/EtOH,9/1) to give product 11c.

Trifluoroacetic acid (3.0 mL) is added to a solution of 11c in CH₂Cl₂(3.0 mL) and the solution is stirred at room temperature for 1 hour. Thesolvent is then evaporated. Saturated aqueous NaHCO₃ solution and CH₂Cl₂are added to the residue. The two phases are separated and the aqueouslayer is extracted with CH₂Cl₂. The organic layers are combined, driedover Na₂SO₄ and concentrated to give 11d.

To a solution of N-methyl-morpholine (0.028 mL) and t-butylisocyanate(25 mg) in CH₂Cl₂ is added 11d (100 mg). The solution is stirred at roomtemperature for 4 hours. The solution is loaded to silica gel andflushed with heptane/acetone (1/1) to give product 11e (91 mg).

Step 11-C:

To a solution of alcohol 11e (91 mg) in CH₂Cl₂ (0.6 mL) at 0° C. isadded DIPEA (0.160 mL) followed by a solution of Py.SO₃ (89 mg) in DMSO(0.6 mL). The solution is stirred at 0° C. for 10 minutes. The mixtureis loaded directed to silica gel column and flushed with heptane/acetone(1/1) to give product 11 (65 mg). Found m/z ES+=534.

Example 12

Step 12-A:

Amino alcohol 12 a is prepared from 8a and cyclobutanone according tothe procedure described for the synthesis of 9f from 8a.

To a solution of Boc-L-t-butyl-gly-OH (277 mg, 1.20 mmol, 1.0 equiv) and12a (200 mg, 1.20 mmol, 1.0 equiv) in CH₂Cl₂ (10.0 mL) at −20° C. isadded HATU (0.55 g, 1.44 mmol, 1.2 equiv) followed by and DIPEA (0.63mL, 3.60 mmol, 3.0 equiv). The solution is stirred at −20° C. for 24hours and 0° C. for 1 h. The reaction mixture is diluted with EtOAc andwashed with 10% citric acid. The phases are separated and the aqueouslayer is extracted with EtOAc. The organic layers are combined andwashed with saturated aqueous NaHCO₃, brine, dried (Na₂SO₄) andconcentrated. The residue is purified by silica gel columnchromatography (hexane/EtOAc, 1/1) to give product 12b.

To a solution of 12b (0.40 g, 1.05 mmol) in acetone (10.0 mL) at 0° C.is added a solution of Jones' reagent (3.0 M, 2.1 mL, 5.3 mmol). Themixture is kept at 0° C. for 1 hour. The reaction is then quenched byslow addition of i-PrOH (3.0 mL) and the mixture is then diluted withEtOAc. The phases are separated and the aqueous layer is extracted withEtOAc. The organic layers are combined, washed with brine, dried(Na₂SO₄) and concentrated to yield 12c.

Step 12-B:

To a solution of acid 12c (0.39 mg, 0.99 mmol) and 7f (206 mg, 0.99mmol, 1.0 equiv) in DMF (8.0 mL) and CH₂Cl₂ (8.0 mL) at 0° C. is addedHATU (452 mg, 1.19 mmol, 1.2 equiv) and N-methyl-morpholine (0.33 mL,2.97 mmol, 3.0 equiv). The solution is stirred at room temperature for 4hours. To the reaction mixture is added saturated aqueous NaHCO₃solution and EtOAc/diethyl ether (1/1). The two phases are separated andthe aqueous layer is extracted with EtOAc. The organic layers arecombined, washed with 1.0 N HCl aq. solution, brine, dried (Na₂SO₄) andconcentrated. The residue is purified by silica gel columnchromatography (hexane/EtOH, 9/1) to give product 12d.

To a solution of 12d (100 mg, 0.18 mmol) in CH₂Cl₂ (1.0 mL) and DMSO(1.0 mL) at 0° C. is added DIPEA (0.19 mL, 1.10 mmol, 6 eq) followed byPy.SO₃ (87 mg, 0.55 mmol, 3 eq). The solution is stirred at 0° C. for 10minutes. The mixture is loaded directly to silica gel column and flushedwith heptane/Acetone (1:1) to give 55 mg of product 12. Found m/zES+=532.

Example 13

Step 13-A:

To a solution of Boc-L-t-butyl-gly-OH (711 mg, 3.08 mmol, 1.0 equiv) andamino alcohol 10 (600 mg, 3.08 mmol, 1.0 equiv) in CH₂Cl₂ (15.0 mL) at−20° C. is added HATU (1.4 g, 3.69 mmol, 1.2 equiv), followed by DIPEA(1.6 mL, 9.2 mmol, 3.0 equiv). The solution is stirred at −20° C. for 24hours, 0° C. for 3 hours and room temperature for 1 hour. The reactionmixture is diluted with EtOAc and washed with 1.0 N HCl aq. solution.The phases are separated and the aqueous layer is extracted with EtOAc.The organic layers are combined and washed with saturated aqueousNaHCO₃, brine, dried over Na₂SO₄ and concentrated. The residue ispurified by silica gel column chromatography (hexane/EtOAc, 1/1) to giveproduct 13a. Found m/z ES+=409.

To a solution of alcohol 13a (890 mg) in acetone (10.0 mL) at −5° C. isadded a solution of Jones' reagent (3.0 M, 5.0 mL). The mixture iswarmed to 0° C. and stirred at this temperature for 2 hours. Thereaction is then quenched by slow addition of i-PrOH (5.0 mL) and themixture is then diluted with EtOAc. The phases are separated and theaqueous layer is extracted with EtOAc. The organic layers are combined,washed with brine, dried (Na₂SO₄) and concentrated to give product 13b.Found m/z ES+=423.

Step 13-B:

To a solution of acid (906 mg, 2.1 mmol) in DMF (8.0 mL) and CH₂Cl₂ (8.0mL) at 0° C. is added HATU (958 mg, 2.5 mmol, 1.2 equiv), amino alcohol(492 mg, 2.4 mmol, 1.1 equiv) and N-methyl-morpholine (0.692 mL, 6.3mmol, 3.0 equiv). The solution is stirred at room temperature for 3hours. The reaction mixture is added saturated aqueous NaHCO₃ solutionand EtOAc/diethyl ether 1/1. The two phases are separated and theaqueous layer is extracted with EtOAc. The organic layers are combined,washed with 1N HCl, brine, dried over Na₂SO₄ and concentrated. The crudematerial is purified by silica gel column chromatography (hexane/EtOH,9/1) to give product 13d. Found m/z ES+=577.

Step 13-C:

To a solution of alcohol 13d (450 mg) in CH₂Cl₂ (0.6 mL) at 0° C. isadded DIPEA (0.504 mL) followed by a solution of Py.SO₃ complex (372 mg)in DMSO (0.6 mL). The solution is stirred at 0° C. for 10 minutes. Themixture is loaded directed to silica gel column and flushed withheptane/Acetone to give product 13e. Found m/z ES+=575.

The product is dissolved in 15 mL of 4.0 M HCl in dioxane. The solutionwas stirred at room temperature for 2 hours. The solution is dilutedwith 50 mL heptane and concentrated to give crude product 13f, which iscarried on to the next step with no purification. Found m/z ES+=475.

Alternative Synthetic Route from 10 to 13d.

To a solution of 10 (1.95 g, 10 mmol) in CH₂Cl₂ (20.0 mL) at roomtemperature added Boc anhydride and DIPEA (0.434 mL, 10.5 mmol, 1.05equiv). The solution is stirred at room temperature for 2 hours. Thesolvent is evaporated and the residue is purified by silica gelchromatography (heptane/EtOAc, 2/1) to give product 13a′ 2.1 g.

To a solution of alcohol 13a′ (3.0 g, 10.2 mmol) in acetone (30.0 mL) at0° C. added Jones' reagent (12.2 mL, 30.5 mmol, 3.0 equiv). The solutionis stirred at 0° C. for 1.0 hour. The reaction is quenched by additionof i-PrOH (5.0 mL). The solution is then diluted with EtOAc andfiltered. The phases are separated and the aqueous layer is extractedwith EtOAc. The organic layers are combined, washed with brine, driedover Na₂SO₄ and concentrated. The crude material is continued to thenext step without further purification.

To a solution of carboxylic acid 13b′ (1.0 g, 3.2 mmol) in CH₂Cl₂ (8.0mL) and DMF (8.0 mL) at 0° C. added 11c (673 mg, 3.2 mmol, 1.0 equiv)followed by HATU (1.45 g, 3.8 mmol, 1.2 equiv) and N-methyl morpholine(1.05 mL, 9.6 mmol, 3.0 equiv). The solution is stirred at roomtemperature for 4 hours. To the solution is added EtOAc and sat. aq.NaHCO₃. The phases are separated and the aqueous layer is extracted withEtOAc. The organic layers are combined, washed with 1.0 N HCl aq.solution, brine, dried over Na₂SO₄ and concentrated. The residue ispurified by silica gel chromatography (heptane/acetone, 1/1) to giveproduct 13c′ 975 mg. Found MS ES+=464.

To a flask containing 13c′ added 10 mL of 4.0 N HCl in dioxane. Thesolution is stirred at room temperature for 1.0 hour. The solvent isthen evaporated give crude product 13d′, which is continued to the nextstep without purification. Found MS ES+=364, ES−=362.

To mixtures of Boc-L-t-butyl-gly-OH (297 mg, 1.29 mmol, 1.0 equiv), 13d′(515 mg, 1.29 mmol, 1.0 equiv) in CH₂Cl₂ (7.0 mL) at −20° C. added HATU(585 mg, 1.54 mmol, 1.2 equiv) and DIPEA (0.696 mL, 4.0 mmol, 3.0equiv). The solution is stirred at −20° C. for 12 hours then 0° C. for1.0 hour. To the solution is added EtOAc and sat. aq. NaHCO₃ solution.The phases are separated and the aqueous layer is extracted with EtOAc.The organic layers are combined, washed with 1.0 N HCl aq. solution,brine, dried over Na₂SO₄ and concentrated. The residue is purified bysilica gel chromatography (heptane/acetone, 1/1) to give product 610 mg.Found MS ES+=577, ES−=575.

Example 13h

To a solution of amine hydrochloride salt 13f (37.5 mg) in CH₂Cl₂ (1.0mL) is added DIPEA (0.012 mL) and a solution of 13g (23 mg) in toluene(1.5 mL). The solution is stirred at room temperature for 2 hours. Thesolution is concentrated and the crude material is purified by silicagel column chromatography to give 20 mg of product 13h. Found m/zES+=741.

Example 13j

To a solution of amine hydrochloride salt 13f (37 mg) in CH₂Cl₂ is addedDIPEA (0.012 mL) and a solution of 13i (21 mg) in toluene (1.5 mL). Thesolution is stirred at room temperature for 2 hours. The solution isconcentrated and the crude material is purified by silica gel columnchromatography to give 6 mg of product 13j. Found m/z ES+=721.

Example 131

To a solution of amine hydrochloride salt 13f (37 mg) in CH₂Cl₂ is addedDIPEA (0.012 mL) and a solution of 13k (26 mg) in toluene (1.5 mL). Thesolution is stirred at room temperature for 2 hours. The solution isconcentrated and the crude material is purified by silica gel columnchromatography to give 15 mg of product 131. Found m/z ES+=777.

Example 13n

To a solution of amine hydrochloride salt 13f (37 mg) in CH₂Cl₂ is addedDIPEA (0.012 mL) and a solution of 13m (18 mg) in toluene (1.5 mL). Thesolution is stirred at room temperature for 2 hours. The solution isconcentrated and the crude material is purified by silica gel columnchromatography to give 29 mg of product 13n. Found m/z ES+=682.

Example 13p

To a solution of amine hydrochloride salt 13f (37 mg) in CH₂Cl₂ is addedDIPEA (0.012 mL) and a solution of 13o (18 mg) in toluene (1.5 mL). Thesolution is stirred at room temperature for 2 hours. The solution isconcentrated and the crude material is purified by silica gel columnchromatography to give 37.6 mg of product 13p. Found m/z ES+=678.

Example 14

Step 14-A:

To a solution of N-Boc amine 13d (690 mg) in dichloromethane (5.0 mL) atroom temperature is added TFA (5.0 mL). The mixture is stirred for 3hours after which the solvent is evaporated in vacuo and dichloromethane(100 mL) is added to the residue. The pH is adjusted to pH 8 by dropwiseaddition of saturated sodium bicarbonate. The layers are separated andthe organic layer with washed with brine, dried over Na₂SO₄, filteredand concentrated to give the product amine 14a. Found m/z ES+=477.

Step 14-B:

To a solution of (S)-2-(tert-butoxycarbonylamino)-2-cyclohexylaceticacid (51.4 mg, 0.2 mmol) in DMF (1.0 mL) and CH₂Cl₂ (1.0 mL) at 0° C. isadded HATU (91 mg, 0.24 mmol, 1.2 equiv), amine 14a (95 mg, 0.2 mmol,1.0 equiv) and N-methyl-morpholine (0.066 mL, 0.6 mmol, 3.0 equiv). Thesolution is stirred at room temperature for 3 hours. To the reactionmixture is added saturated aqueous NaHCO₃ solution and EtOAc/diethylether 1/1. The two phases are separated and the aqueous layer isextracted with EtOAc. The organic layers are combined, washed with 1NHCl, brine, dried over Na₂SO₄ and concentrated. The crude material ispurified by silica gel column chromatography (hexane/EtOH, 9/1) to giveBoc-protected amine (Found m/z ES+=716). The product is dissolved indichloromethane (5 mL) at room temperature and TFA (5 mL) is added. Themixture is stirred for 3 hours after which the solvent is evaporated invacuo. The residue is dissolved in dichloromethane (100 mL). The pH isadjusted to pH 8 by dropwise addition of saturated sodium bicarbonate.The layers are separated and the organic layer with washed with brine,dried over Na₂SO₄, filtered and concentrated to give the product 14b.Found m/z ES+=616.

Step 14-C:

To a solution of pyrazine-2-carboxylic acid (20 mg, 0.16 mmol) in DMF(1.0 mL) and CH₂Cl₂ (1.0 mL) at 0° C. is added HATU (73 mg, 0.19 mmol,1.2 equiv), amine 14b (100 mg, 0.16 mmol, 1.0 equiv) andN-methyl-morpholine (0.053 mL, 0.48 mmol, 3.0 equiv). The solution isstirred at room temperature for 3 hours. To the reaction mixture isadded saturated aqueous NaHCO₃ solution and EtOAc/diethyl ether 1/1. Thetwo phases are separated and the aqueous layer is extracted with EtOAc.The organic layers are combined, washed with 1N HCl, brine, dried overNa₂SO₄ and concentrated. The crude material is purified by silica gelcolumn chromatography (hexane/EtOH, 9/1) to give product 14c. Found m/zES+=722.

To a solution of alcohol 14c (110 mg) in CH₂Cl₂ (0.6 mL) at 0° C. isadded DIPEA (0.160 mL) followed by a solution of sulfur trioxidepyridine complex (89 mg) in DMSO (0.6 mL). The solution is stirred at 0°C. for 10 mines. The mixture is loaded directly onto a silica gel columnand flushed with heptane/Acetone to give product 14d (71 mg). Found m/zES+=720.

Example 15

Scheme:

Step 15-A:

To a solution of amine (87 mg, 0.2 mmol, 1.0 equiv) in IPA (0.4 mL) atroom temperature is added 2-bromo-pyrimidine (32 mg, 0.2 mmol, 1.0equiv) and DIPEA (0.034 mL, 0.2 mmol, 1.0 equiv). The solution is heatedat 80° C. for 24 hours. The crude material is purified by silica gelchromatography (heptane/acetone, 1/1) to give desired product.

Found m/z ES+=515.

Step 15-B:

To a solution of 15a (90 mg) in CH₂Cl₂ (0.6 mL) add DIPEA (0.12 mL) anda solution of Py.SO₃ (80 mg) in DMSO (0.6 mL). The solution is stirredat rt for 10 mins. The solution is loaded to silica gel and flushed withheptane/acetone (1/1) to give 28 mg of product 15. Found m/z ES+=513.

Example 16

Synthesis of Thiazole:

Step 16-A:

Benzoyl isothiocyanate (162 mg) is added to a solution of amine (400 mg)in acetone (4.0 mL). The solution is heated at 70° C. for 2 hours.Potassium carbonate (40 mg), water (0.4 mL) and MeOH (4.0 mL) are thenadded to the solution. The solution is then heated at 80° C. for 4hours. The mixture is concentrated and the crude residue is purified bysilica gel chromatography (CH₂Cl₂/MeOH, 4/1) to give thioureaintermediate 16a. Found m/z ES+=497.

Step 16-B:

The thiourea (70 mg) and 2-bromo-1-pyrazin-2-yl-ethanone (30 mg) aredissolved in ethanol (0.5 mL) and the solution is heated to reflux for 1hour. The crude material is purified by silica gel chromatography(CH₂Cl₂/EtOH, 9/1) to give product 16b. Found m/z ES+=598.

Step 16-C:

To a solution of 16b (70 mg) in CH₂Cl₂ (1.0 mL) add DIPEA (0.12 mL) anda solution of Py.SO₃ (80 mg) in DMSO (0.6 mL). The solution is stirredat rt for 10 mins. The solution is loaded to silica gel and flushed withheptane/acetone (1/1) to give 25 mg of product 16. Found m/z ES+=513.

Example 17

Step 17-A:

To a solution of 17a (5.31 g, 11.86 mmol) in CH₂Cl₂ (40 mL) at 0° C. addsat. aq. NaHCO₃ (40 mL) and CSCl₂ (1.1 mL, 14.23 mmol) is added. Themixture is stirred at room temperature for 30 minutes. The phases areseparated and the organic layer is washed with brine, dried over Na₂SO₄,and concentrated. The crude material is purified by silica gelchromatography (heptane/EtOAc, 1/1) to give product 17b (1.20 g, 21%yield) as light yellow solid. Found m/z ES+=491.

Step 17-B:

To a solution of 17b (60 mg, 0.122 mmol) in dioxane is added PPh₃ (38.6mg, 0.147 mmol) and followed by 1-azidopropan-2-one (14.5 mg, 0.147mmol). The solution is heated at 90° C. for 1 hour. Then2-methyl-propane-1,2 diamine (0.20 mL) is added and the solution isheated at 50° C. for 30 minutes. The crude mixture is separated bysilica gel column chromatography (CH₂Cl₂/EtOH, 4/1) to afford 17c (22mg). Found m/z ES+=530.

Step 17-C:

To a solution of 17c (22 mg, 0.042 mmol) in CH₂Cl₂ add DIPEA (0.044 mL,0.252 mmol) and DMSO (0.5 mL). Then the solution is cooled to 0° C. andPy.SO₃ (20 mg, 0.125 mmol) is added. The solution is stirred at 0° C.for 10 minutes. The mixtures are separated by chromatography(Heptane/Acetone, 1/1) to afford 17 (5 mg). Found m/z ES+=528.

Example 18

Scheme:

Step 18-A:

A solution of 18a (89 mg, 0.2 mmol) in CH₂Cl₂ (1.0 mL) is addedcyclohexanone (0.22 mmol, 0.023 mL). The solution is stirred for 20minutes at room temperature after which sodium triacetoxy borohydride(0.4 mmol, 84 mg) is added and stirred for another 20 minutes. To thereaction mixtures add sat. aq. NaHCO₃ solution. The organic layer isseparated from aqueous layer and the aqueous layer is extracted withdichloromethane (3×10 mL). The organic layers are combined, dried(Na₂SO₄) and concentrated to give 97 mg of 18b.

Step 18-B:

A solution of 18b (97 mg, 0.183 mmol) in DCM is added Et₃N (0.366 mmol,51 μL) and (Boc)₂O (0.274 mmol, 60 mg). The solution is stirred at roomtemperature for an hour after which it is washed with 1.0 N HCl aq.solution (1 mL), sat. aq. NaHCO₃ solution (1 mL) and brine. The organiclayer is dried over Na₂SO₄, and concentrated. The residue is purified bysilica gel column chromatography (eluent: acetone/heptane, 1:1) to give95 mg of 18c.

Step 18-C:

To a solution of 18c (73 mg, 0.12 mmol) in CH₂Cl₂ (0.5 mL), DIPEA (81μL, 0.46 mmol) and DMSO (0.5 mL) are added. Then the solution is cooledto 0° C. and Py.SO₃ (37 mg, 0.23 mmol) is added. The solution is stirredat 0° C. for 10 minutes. The mixtures are separated by silica gelchromatography (Heptanes/Acetone, 1/1) to afford 67 mg of 18d.

Step 18-D:

The product 18d (66 mg, 0.104 mmol) is dissolved in dioxane (0.2 mL) andthe solution is added 4.0 N HCl in dioxane (0.105 mL) at 0° C. Thereaction mixture is stirred at rt for 24 hours after which the reactionmixture is concentrated. The residue is dissolved in DCM and thesolution is washed with sat. NaHCO₃ aq. solution, brine. The organiclayer is dried over Na₂SO₄, chromatographed (Eluent: Acetone/heptane,1:1) to give 33.5 mg of 18.

Example 19

Step 19-A:

Intermediate 19a is prepared according to the procedure described forthe synthesis of 13d. Found MS ES+=491.

Step 19-B:

To a solution of Boc-L-cyclohexyl-gly-OH (0.391 g, 1.53 mmol) and 19a(800 mg, 1.53 mmol, 1.0 equiv) in CH₂Cl₂ (7.0 mL) and DMF (7.0 mL) at 0°C. added HATU (697 mg, 1.8 mmol, 1.2 equiv) and N-methyl morpholine(0.505 mL, 4.6 mmol, 3.0 equiv). The solution is stirred at roomtemperature for 4 hours. To the solution is added EtOAc and sat. aq.NaHCO₃. The phases are separated and the aqueous layer is extracted withEtOAc. The organic layers are combined, washed with 1.0 N HCl aq.solution, brine, dried over Na₂SO₄ and concentrated. The residue ispurified by silica gel chromatography (heptane/acetone, 1/1) to giveproduct 19b. Found MS ES+=730, ES−=728.

To a flask containing 19b (1.02 g) added 4.0 N HCl in dioxane (10.0 mL).The solvent is evaporated to give crude material 19c, which is continuedto the next step without purification. Found MZ ES+=630, ES−=628.

Step 19-C:

To a solution of pyrazine-2-carboxylic acid (0.175 g, 1.40 mmol) and 19c(938 mg, 1.40 mmol, 1.0 equiv) in CH₂Cl₂ (7.0 mL) and DMF (3.0 mL) at 0°C. added HATU (639 mg, 1.7 mmol, 1.2 equiv) and N-methyl morpholine(0.461 mL, 4.2 mmol, 3.0 equiv). The solution is stirred at roomtemperature for 4 hours. To the solution is added EtOAc and sat. aq.NaHCO₃. The phases are separated and the aqueous layer is extracted withEtOAc. The organic layers are combined, washed with 1.0 N HCl aq.solution, brine, dried over Na₂SO₄ and concentrated. The residue ispurified by silica gel chromatography (heptane/acetone, 1/1) to giveproduct 19d. Found MZ ES+=736, ES−=734.

Step 19-D:

To a solution of 19d (670 mg, 0.91 mmol) in CH₂Cl₂ (2.0 mL) at 0° C.added DIPEA (0.95 mL, 5.46 mmol, 6.0 equiv) followed by a solution ofPy.SO₃ (440 mg, 2.73 mmol, 2.0 equiv) in DMSO (2.0 mL). The solution isstirred at 0° C. for 10 minutes, after which it is added sat. aq. NH₄Clsolution and EtOAc. The phases are separated and the aqueous layer isextracted with EtOAc. The organic layers are combined, dried over Na₂SO₄and concentrated. The residue is purified by silica gel chromatography(heptane/acetone, 1/1) to give 71 mg of 19. Found MZ ES+=734, ES−=732.

Example 20

To mixtures of 19a (75 mg, 0.14 mmol) in CH₂Cl₂ (1 mL) added DIPEA (0.05mL, 0.29 mmol) at 0° C., 20a (0.18 mmol, in toluene solution). Thesolution is stirred at 0° C. for 30 min after which it is quenched byaddition of citric acid (10% aq. solution, 5 mL) and EtOAc. The phasesare separated and the aqueous layer is extracted with EtOAc. Thecombined organic layers are washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue is purified by silica gelchromatography (heptane/acetone, 1/1) to give 59 mg of 20. Found MZ,ES+=752, ES−=750.

Example 21

Step 21-A:

Synthesis of compound 21b is carried out in a three step sequencefollowing a literature procedure by Busacca, C. A.; Grossbach, D.Spinelli, E. Tetrahedron: Asymmetry, 2000, 11(9), 1907-1910.

Step 21-B:

To a solution of N-Carbobenzyloxy-2-methylalanine 21a (817 mg, 3.44mmol, 1.2 equiv) and amine 21b (620 mg, 2.87 mmol, 1.0 equiv) in CH₂Cl₂(15.0 mL) at 0° C. is added HATU (1.31 g, 3.44 mmol, 1.2 equiv),followed by DIPEA (1.25 mL, 7.16 mmol, 2.5 equiv). The solution isstirred overnight at RT. The reaction mixture is diluted with EtOAc (75mL) and washed with 1.0 N HCl (2×10 mL). The phases were separated andthe aqueous layer extracted with EtOAc (2×50 mL). The organic layers arecombined and washed with saturated aqueous NaHCO₃ (50 mL), brine (50mL), dried over Na₂SO₄ and concentrated. The residue is purified bysilica gel column chromatography (hexane/EtOAc, 1/1) to give 1g of theproduct 21c. ESMS; [M+H]⁺=436.

Step 21-C:

The N-Boc protected amine 21c (388 mg, 0.89 mmol) is dissolved in HCl(2.5 mL, 4.0 M HCl in dioxane) and the solution stirred at roomtemperature for 2 hours. The solution is diluted with 50 mL heptane andconcentrated to give crude product 21d, This compound did not requirepurification and is used directly in the next step. ESMS; [M+H]⁺=335.

Step 21-D:

Amine 21d (169 mg, 0.46 mmol) is dissolved in Dichloromethane (2.3 mL)and the solution cooled to 0° C. Saturated NaHCO₃ (2.3 mL) is added andthe solution stirred vigorously for 5 min. Stirring is stopped andPhosgene (0.46 mL, 0.92 mmol of 2M solution in Toluene) is added to thelower Dichloromethane layer and vigorous stirring is continued for 1 hat room temperature. The solution is diluted with Dichloromethane (10mL), the layers separated and the organic layer collected and dried overNa₂SO₄. The solution is then evaporated to dryness and is used directlyin the next step.

A solution of the isocyanate of 21d in CH₂Cl₂ (7 mL) generated above isadded to a cooled solution (0° C.) of amine hydrochloride salt 21e (82mg, 0.17 mmol) in CH₂Cl₂ (7 mL). DIPEA (0.24 mL) is then added and thesolution stirred at room temperature for 2 hours. The solution is thenconcentrated and the crude material purified by silica gel columnchromatography (Acetone: Heptane 40%-75% acetone) to give 50 mg ofproduct 21f. ESMS; [M+H]⁺=836.

Step 21-E:

Benzyloxycarbamate 21f (11 mg, 0.013 mmol) is dissolved in EtOAc (3 mL).Air was evacuated and flask purged with N₂. Palladium (10% on C, 2 mg)is added and the mixture fitted with H₂ balloon. The reaction is allowedto proceed for 5 h and then stopped by filtering the mixture through acelite bed. The filtrate is then concentrated. HCl (4M HCl in Dioxane, 2mL) is added and the solution stirred for 2 min and then evaporated todryness. The solid sample is washed with heptane (5 mL) and EtOAc (2 mL)then dissolved in H₂O (3 mL) and lyophilized overnight to afford 7 mg ofa white solid 21. ESMS; [M+H]⁺=702.

Example 22

Scheme:

Step 22-A:

To a solution of Boc-L-cyclohexyl-gly-OH (2.0 g, 7.8 mmol) in CH₂Cl₂(15.0 mL) at room temperature add HATU (3.5 g, 9.3 mmol, 1.2 equiv),morpholine (0.679 mL, 7.8 mmol, 1.0 equiv) and N-methyl-morpholine (2.6mL, 23.4 mmol, 3.0 equiv). The solution is stirred at room temperaturefor 3 hours. The solution is then added EtOAc and sat. aq. NaHCO₃. Thephases are separated and the organic phase is washed with 1.0 N aq. HCl,and brine. The solution is dried over Na₂SO₄ and concentrated. Theresidue is purified by silica gel column chromatography, heptane/EtOAc,1/1 to give product 22a 1.2 g.

Step 22-B:

The product 22a is dissolved in 4.0 N HCl in dioxane and the solution isstirred at room temperature for 1 hour. The solution is thenconcentrated to dryness to give product 22b.

To a solution of 4-nitrophenyl chloroformate (201 mg, 1.1 mol, 1.0equiv) in CH₂Cl₂ at room temperature added 22b (263 mg, 1.0 mmol, 1.0equiv) and pyridine (0.242 mL, 3.0 mmol, 3.0 equiv). After stirred atroom temperature for 1 h, the solution is directly loaded to silica gelcolumn and the column is flushed with heptane/EtOAc (1/1 to 100% EtOAc)to give product 22c 315 mg. Found ES+=392.

Step 22-C:

To a solution of 22c (49 mg 0.127 mmol, 1.0 equiv) in CH₂Cl₂ (0.5 mL)added 19c (67 mg, 0.127 mmol, 1.0 equiv) and TEA (0.042 mL, 0.3 mmol,3.0 equiv). The solution is stirred at room temperature for 2 hours. Thesolution is then loaded to silica gel column and the column is flushedwith heptane/acetone (1/1) to give product 22d 80 mg. Found m/z, ES+=743

Step 22-D:

To a solution of 22d (80 mg, 0.107 mmol) in CH₂Cl₂ (1.0 mL) add DIPEA(0.093 mL, 0.535 mmol, 5.0 equiv) and a solution of Py.SO₃ (51 mg, 0.323mmol, 3.0 equiv) in DMSO (0.5 mL). The solution is stirred at roomtemperature for 10 minutes. The solution is loaded to silica gel columnand the column is flushed with heptane/acetone (1/1) to give product 2275 mg. Found m/z, ES+=741.

Example 23

Scheme:

Step 23-A:

To a solution of sulfuryl chloride (1.62 mL, 20.0 mmol, 1.0 equiv) inCHCl₃ (20.0 mL) at 0° C. slowly added a solution of morpholine (1.7 mL,20.0 mmol, 1.0 equiv) and TEA (2.78 mL) in CHCl₃ (5.0 mL) over 1 hour.The solution is stirred at 0° C. for 1 hour then room temperature for 1hour. The solution is concentrated and then partitioned between etherand 1.0 N aq. HCl solution. The phases are separated and the organiclayer is washed with brine. The organic layer is dried over Na₂SO₄ andconcentrated to give product 23a (2.5 g).

Step 23-B:

To a solution of 23a (559 mg, 3.0 mmol, 1.0 equiv) in CH₂Cl₂ (10.0 mL)at −20° C. added 23b (648 mg, 3.0 mmol, 1.0 equiv) and TEA (0.836 mL,6.0 mmol, 2.0 equiv). The solution is stirred at room temperature for 24hours and at 40° C. for 4 hours. The solution is loaded to silica gelcolumn and the column is flushed with heptane/EtOAc (1/1) to giveproduct 23c (760 mg).

Step 23-C:

To a solution of 23c (760 mg, 2.07 mmol, 1.0 equiv) in DMF (6.0 mL) at0° C. add Cs₂CO₃ (2.0 g, 6.2 mmol, 3.0 equiv) and MeI (0.154 mL, 2.48mmol, 1.2 equiv). The solution is stirred at room temperature for 1.0hours. The solution is filtered and the solvent is evaporated. Theresidue is purified by silica gel column chromatography, heptane/EtOAc(1/2) to give product 23d (510 mg).

Step 23-D:

The product 23d is dissolved in 4.0 N HCl in dioxane and stirred at roomtemperature for 1 hour. The solution is then concentrated to dryness togive product 23e.

To a solution of 4-nitrophenyl chloroformate (179 mg, 0.89 mol, 1.0equiv) in CH₂Cl₂ (4.0 mL) at room temperature added 23e (270 mg, 0.89mmol, 1.0 equiv) and pyridine (0.144 mL, 2.0 mmol, 2.0 equiv). Thesolution is stirred at room temperature for 1 hour. The solution isloaded to silica gel column and the column is flushed with heptane/EtOAc(1/1 to 100% EtOAc) to give product 23f (210 mg).

Step 23-E:

To a solution of 23f (63 mg, 0.14 mmol, 1.0 equiv) in CH₂Cl₂ (1.0 mL)added 19c (75 mg, 0.14 mmol, 1.0 equiv) and TEA (0.031 mL, 0.42 mmol,3.0 equiv). The solution is stirred at room temperature for 2 hours. Thesolution is then loaded to silica gel column and the column is flushedwith heptane/acetone (1/1 to 100% acetone) to give product 23g 101 mg.Found m/z, ES+=796.

Step 23-F:

To a solution of 23g (101 mg) in CH₂Cl₂ (1.0 mL) add DIPEA (0.120 mL)and a solution of Py.SO₃ (70 mg) in DMSO (0.5 mL). The solution isstirred at room temperature for 10 minutes. The solution is loaded tosilica gel column and the column is flushed with heptane/acetone (1/1)to give product 22 71 mg. Found m/z, ES+=794.

BIOLOGICAL ACTIVITY Example 24 HCV NS3-4A Protease Assay

The inhibitory activity of certain compounds of Table A against HCVNS3-4A serine protease is determined in a homogenous assay using thefull-length NS3-4A protein (genotype la, strain HCV-1) and acommercially available internally-quenched fluorogenic peptide substrateas described by Taliani, M., et al. 1996 Anal. Biochem. 240:60-67, whichis incorporated by reference in its entirety.

Example 25 Luciferase-Based HCV Replicon Assay

The antiviral activity and cytotoxicity of certain compounds of Table Ais determined using a subgenomic genotype 1b HCV replicon cell line(Huh-Luc/neo-ET) containing a luciferase reporter gene, the expressionof which is under the control of HCV RNA replication and translation.Briefly, 5,000 replicon cells are seeded in each well of 96-well tissueculture plates and are allowed to attach in complete culture mediawithout G418 overnight. On the next day, the culture media are replacedwith media containing a serially diluted compound of Table A in thepresence of 10% FBS and 0.5% DMSO. After a 48-h treatment with thecompound of Table A, the remaining luciferase activities in the cellsare determined using BriteLite reagent (Perkin Elmer, Wellesley, Mass.)with a LMaxII plate reader (Molecular Probe, Invitrogen). Each datapoint represents the average of four replicates in cell culture. IC₅₀ isthe concentration of the at which the luciferase activity in thereplicon cells is reduced by 50%. The cytotoxicity of the compound ofTable A is evaluated using an MTS-based cell viability assay.

Compounds in Table A supra have been tested in at least one of theprotease assay of Example 24 or the replicon assay of Example 25 andexhibit an IC₅₀ of less than about 10 μM or less in at least one of theassays recited in Example 24 and 25.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments and methods described herein. Such equivalents are intendedto be encompassed by the scope of the following claims.

INCORPORATION BY REFERENCE

The entire contents of all patents, published patent applications andother references cited herein are hereby expressly incorporated hereinin their entireties by reference. The entire contents of copendingprovisional patent applications U.S. Ser. No. 60/791,611, U.S. Ser. No.60/791,578, and U.S. Ser. No. 60/791,320, each of which was filed onApr. 11, 2006, and non-provisional patent applications claiming thebenefit therefrom are expressly incorporated herein, in their entirety,as applied to the compounds of the present invention.

1. A compound of the Formula I:

and pharmaceutically acceptable salt and stereoisomer thereof; wherein yis 0 or 1; n and p are each independently selected from 0, 1 or 2; R¹⁴is C(O) or SO₂; R¹, R², W, R¹³ and V are each, independently, selectedfrom hydrogen or from the group consisting of alkyl, alkyl-aryl,heteroalkyl, heterocyclyl, heteroaryl, aryl-heteroaryl,alkyl-heteroaryl, cycloalkyl, alkyloxy, alkyl-aryloxy, aryloxy,heteroaryloxy, heterocyclyloxy, cycloalkyloxy, amino, alkylamino,arylamino, alkyl-arylamino, arylamino, heteroarylamino, cycloalkylamino,carboxyalkylamino, mono- and di-alkylcarboxamide, aralkyloxy andheterocyclylamino; each of which may be further independentlysubstituted one or more times with X¹ and X²; wherein X¹ is alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl, heterocyclyl,heterocyclylalkyl, aryl, alkylaryl, aralkyl, aryloxy, arylthio,arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl, orheteroaralkyl; wherein X¹ can be independently substituted with one ormore X² moieties which can be the same or different and areindependently selected; wherein X² is hydroxy, oxo, alkyl, cycloalkyl,spirocycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy,thio, alkylthio, amino, mono- and di-alkylamino, arylamino,alkylsulfonyl, arylsulfonyl, alkylsulfonamido, arylsulfonamido, carboxy,carbalkoxy, carboxamido, alkoxycarbonylamino, alkoxycarbonyl,alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano, or nitro;wherein each X₂ residue selected to be alkyl, alkoxy, and aryl can beunsubstituted or optionally independently substituted with one or moremoieties which can be the same or different and are independentlyselected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkyl-alkyl,heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, aralkyl,arylheteroaryl, heteroaryl, heterocyclylamino, alkylheteroaryl andheteroaralkyl; W is also selected from the group consisting ofC(O)—C(O)H, C(═N—O—R₂₄)—C(O)-amine, C(O)—C(O)-amine,C(O)NR₂₄S(O)_(p)R₂₄, C(O)NR₂₄S(O)_(p)N(R₂₄)₂ andC(O)—[C(O)]_(a)-heterocycle, wherein the heterocycle may beindependently substituted one or more times with aryl, C₁₋₄-alkyl,C₁₋₄-alkyl substituted by one or more halogen atoms, andC₃₋₆-cycloalkyl, wherein a is 0 or 1, wherein each R₂₄ is independentlyselected from hydrogen or the group consisting of C₁₋₄-alkyl,C₃₋₆-cycloalkylC₀₋₄alkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heterocycle, each of which may beindependently substituted one or more times with a halogen atom orC₁₋₄-alkyl; V is also selected from the group consisting of -Q¹-Q²,wherein Q¹ is absent, C(O), N(H), N(C₁₋₄-alkyl), C═N(CN), C═N(SO₂CH₃),C═N—COH—C₁₋₄-alkyl, or C═N—COH, and Q² is hydrogen or is selected fromthe group consisting of C₁₋₄-alkyl, O—C₁₋₄-alkyl, NH₂, N(H)—C₁₋₄-alkyl,N(C₁₋₄-alkyl)₂, SO₂-aryl, SO₂—C₁₋₄-alkyl, C₃₋₆-cycloalkyl-C₀₋₄-alkyl,aryl, heteroaryl and heterocycle, each of which may be independentlysubstituted one or more times with a halogen atom, C₁₋₄-alkyl,C₁₋₄-alkyl substituted by one or more halogen atoms, or C₃₋₆-cycloalkyl;or R¹ and R² may together form a 3, 4, 5, 6 or 7-membered ring that isaromatic or non-aromatic and may contain one or more heteroatoms,wherein the ring may be further substituted one or more times; R³ isselected from the group consisting of hydrogen, C₁₋₄-alkyl andC₃₋₆cycloalkylC₀₋₄alkyl; X is O, S, N, NR^(S), CR⁵ or CR⁵R^(5a); R⁴represents 0-4 substituents, each of which is independently selectedfrom hydrogen or from the group consisting of C₁₋₄-alkyl,C₃₋₆-cycloalkyl, aryl, heterocycle and heteroaryl, each of which may beindependently substituted one or more times with a halogen atom orC₁₋₄-alkyl; R⁵ is selected from hydrogen or oxo or from the groupconsisting of hydroxyl, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₃₋₈-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl, heterocycle-C₀₋₄-alkyl,heteroaryl-C₀₋₄-alkyl, C₃₋₈-cycloalkyloxy, aryloxy, and heteroaryloxyeach of which may be independently substituted one or more times with ahalogen atom, aryl, trihalomethyl, or C₁₋₄-alkyl; R^(5a) is hydrogen oris selected from the group consisting of hydroxyl, C₁₋₈-alkyl,C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyland heteroaryl-C₀₋₄-alkyl, or R⁴ and R⁵ may together form a fuseddimethyl cyclopropyl ring, a fused cyclopentane ring, a fused phenylring or a fused pyridyl ring, each of which may be substituted with ahalogen atom, aryl, trihalomethyl, or C₁₋₄-alkyl; or R⁵ and R⁶ maytogether form a fused dimethyl cyclopropyl ring, a fused cyclopentanering, a fused phenyl ring or a fused pyridyl ring, each of which may besubstituted with a halogen atom, aryl, trihalomethyl, or C₁₋₄-alkyl; orR⁵ and R^(5a) may together form a spirocyclic ring having between 3 and7 ring atoms and having 0, 1, or 2 ring heteroatoms, which is optionallysubstituted by 0-4 substituents selected from cyano, halogen, hydroxyl,amino, thiol, C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl,C₁₋₈-alkoxy-C₀₋₄alkyl, C₁₋₈-haloalkyl, C₂₋₈-haloalkenyl,C₂₋₈-haloalkynyl, C₁₋₈-haloalkoxy, C₁₋₈-alkylthio, C₁₋₈-alkylsulfonyl,C₁₋₈-alkylsulfoxy, C₁₋₈-alkanoyl, C₁₋₈-alkoxycarbonyl, aryl-C₀₋₄-alkyl,heteroaryl-C₀₋₄-alkyl, COOH, C(O)NH₂, mono- anddi-C₁₋₄-alkyl-carboxamide, mono- and di-C₁₋₄-alkyl-amino-C₀₋₄alkyl,SO₃H, SO₂NH₂, and mono- and di-C₁₋₄-alkylsulfonamide, R⁶ and R⁷ areeach, independently, selected from the group consisting of hydrogen,hydroxy, amino, C₁₋₄alkyl, C₁₋₄alkoxy, and mono- and di-C₁₋₄alkylamino,and C₃₋₆cycloalkylC₀₋₄alkyl; R⁸, R⁹, R¹⁰, R¹¹ and R¹² are each,independently, selected from the group consisting of hydrogen,C₁₋₄-alkyl and C₃₋₆cycloalkylC₀₋₄alkyl; or R⁶ and R⁷ may together form aspirocyclic ring having between 3 and 7 ring atoms and having 0, 1, or 2ring heteroatoms, which is optionally substituted by 0-4 substituentsselected from cyano, halogen, hydroxyl, amino, thiol, C₁₋₈-alkyl,C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₁₋₈-alkoxy-C₀₋₄-alkyl, C₁₋₈-haloalkyl,C₂₋₈-haloalkenyl, C₂₋₈-haloalkynyl, C₁₋₈-haloalkoxy, C₁₋₈-alkylthio,C₁₋₈-alkylsulfonyl, C₁₋₈-alkylsulfoxy, C₁₋₈-alkanoyl,C₁₋₈-alkoxycarbonyl, C₃₋₇-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl,heteroaryl-C₀₋₄-alkyl, COOH, C(O)NH₂, mono- anddi-C₁₋₄-alkyl-carboxamide, mono- and di-C₁₋₄-alkyl-amino-C₀₋₄alkyl,SO₃H, SO₂NH₂, and mono- and di-C₁₋₄-alkylsulfonamide, or twosubstituents taken together form a fused or spirocyclic 3 to 7 memberedring having 0, 1 or 2 ring heteroatoms selected from N, O and S, whichfused or spirocyclic ring has 0 to 2 independently selected substituentsselected from halogen, C₁₋₄alkyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, mono- anddi-C₁₋₄-alkylamino, mono- and di-C₁₋₄-alkyl-carboxamide,C₁₋₄-alkoxycarbonyl, and phenyl; or R³ and W may together form a 3, 4,5, 6 or 7-membered ring that is aromatic or non-aromatic and may containone or more heteroatoms, wherein the ring may be further substituted oneor more times; and or when y is 0, R¹⁰ and V may together form a 3, 4,5, 6 or 7-membered ring that is aromatic or non-aromatic and may containone or more heteroatoms, wherein the ring may be further substituted oneor more times.
 2. The compound of claim 1, wherein y is 0 or 1; n is 0or 1; R¹⁴ is C(O) or SO₂ R¹ is selected from the group consisting of Hand C₁₋₄-alkyl; R² is selected from the group consisting of C₁₋₄-alkyl,C(O)C₁₋₄-alkyl, C(O)OC₁₋₄-alkyl, and C₃₋₆cycloalkylC₀₋₄alkyl; or R¹ andR² together form a cyclopropane ring; W is also selected from the groupconsisting of C(O)—C(O)H, C(═N—O—R₂₄)—C(O)-amine, C(O)—C(O)-amine,C(O)NR₂₄S(O)_(p)R₂₄, C(O)NR₂₄S(O)_(p)N(R₂₄)₂ andC(O)-[C(O)]_(a)-heterocycle, wherein the heterocycle may beindependently substituted one or more times with aryl, C₁₋₄-alkyl,C₁₋₄-alkyl substituted by one or more halogen atoms, andC₃₋₆-cycloalkyl, wherein a is 0 or 1, wherein each R₂₄ is independentlyselected from hydrogen or from the group consisting of C₁₋₄-alkyl,C₃₋₆cycloalkylC₀₋₄alkyl, substituted or unsubstituted aryl andsubstituted or unsubstituted heterocycle, each of which may beindependently substituted one or more times with a halogen atom orC₁₋₄-alkyl; p is 0, 1 or 2; R³ is selected from the group consisting ofH and C₁₋₄-alkyl; X is O, NR⁵ or CR⁵R^(5a); R⁴ is selected from hydrogenor from the group consisting of C₁₋₄-alkyl, C₃₋₆-cycloalkyl, aryl,heterocycle and heteroaryl, each of which may be independentlysubstituted one or more times with a halogen atom or C₁₋₄-alkyl; R⁵ isselected from hydrogen or oxo or from the group consisting of hydroxyl,C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₃₋₈-cycloalkyl-C₀₋₄-alkyl,heterocycle-C₀₋₄-alkyl and heteroaryl-C₀₋₄-alkyl, each of which may beindependently substituted one or more times with a halogen atom, aryl,trihalomethyl, or C₁₋₄-alkyl; R^(5a) is selected from hydrogen or fromthe group consisting of hydroxyl, C₁₋₈-alkyl, C₂₋₈-alkenyl,C₂₋₈-alkynyl, C₃₋₈-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl andheteroaryl-C₀₋₄-alkyl, or R⁴ and R⁵ may together form a fused dimethylcyclopropyl ring, a fused cyclopentane ring, a fused phenyl ring or afused pyridyl ring, each of which may be substituted with a halogenatom, aryl, trihalomethyl, or C₁₋₄-alkyl; or R⁵ and R^(5a) may togetherform a spirocyclic ring having between 3 and 7 ring atoms and having 0,1, or 2 ring heteroatoms, which is optionally substituted by 0-4substituents selected from cyano, halogen, hydroxyl, amino, thiol,C₁₋₈-alkyl, C₂₋₈-alkenyl, C₂₋₈-alkynyl, C₁₋₈-alkoxy-C₀₋₄alkyl,C₁₋₈-haloalkyl, C₂₋₈-haloalkenyl, C₂₋₈-haloalkynyl, C₁₋₈-haloalkoxy,C₁₋₈-alkylthio, C₁₋₈-alkylsulfonyl, C₁₋₈-alkylsulfoxy, C₁₋₈-alkanoyl,C₁₋₈-alkoxycarbonyl, C₃₋₇-cycloalkyl-C₀₋₄-alkyl, aryl-C₀₋₄-alkyl,heteroaryl-C₀₋₄-alkyl, COOH, C(O)NH₂, mono- anddi-C₁₋₄-alkyl-carboxamide, mono- and di-C₁₋₄-alkyl-amino-C₀₋₄alkyl,SO₃H, SO₂NH₂, and mono- and di-C₁₋₄-alkylsulfonamide, R⁸, R¹⁰ and R¹¹are each, independently, selected from the group consisting of H andC₁₋₄-alkyl; R⁶ and R⁷ are each, independently, selected from the groupconsisting of hydrogen, hydroxy, amino, C₁₋₄alkyl, C₁₋₄alkoxy, and mono-and di-C₁₋₄alkylamino; R¹³ is H; R⁹ and R¹² are each, independently,selected from the group consisting of hydrogen, C₁₋₄-alkyl andC₃₋₆-cycloalkyl; and V is also selected from the group consisting of-Q¹-Q², wherein Q¹ is absent, C(O), N(H), N(C₁₋₄-alkyl), C═N(CN),C═N(SO₂CH₃), C═N—COH—C₁₋₄-alkyl, or C═N—COH, and Q² is hydrogen or isselected from the group consisting of C₁₋₄-alkyl, O—C₁₋₄-alkyl, NH₂,N(H)—C₁₋₄-alkyl, N(C₁₋₄-alkyl)₂, SO₂-aryl, SO₂—C₁₋₄-alkyl,C₃₋₆-cycloalkyl-C₀₋₄-alkyl, aryl, heteroaryl and heterocycle, each ofwhich may be independently substituted one or more times with a halogenatom, C₁₋₄-alkyl, C₁₋₄-alkyl substituted by one or more halogen atoms,or C₃₋₆-cycloalkyl; or R³ and W can together form a 6-membered ring ofthe formula II:

wherein formula II may be further substituted; or when y is 0, R¹⁰ and Vcan form a cyclopropyl ring that may be further substituted by an amidegroup.
 3. The compound of claim 1, wherein R¹⁴ is C(O).
 4. The compoundof claim 1, wherein y is 0, and R¹⁰ and V form a cyclopropyl ring thatis substituted with C(O)N(H)-pyrazine.
 5. The compound of claim 1,wherein R⁴, R⁶ and R⁷ are hydrogen, and R⁵ is arylC₀₋₃alkyl,heteroaryloxy, or heteroarylC₀₋₃alkyl, wherein aryl and heteroaryl maybe independently substituted one or more times with a halogen atom,aryl, trihalomethyl, C₃₋₆-cycloalkyl or C₁₋₄-alkyl.
 6. The compound ofclaim 1, wherein R¹ and R², are independently selected from hydrogen orfrom the group consisting of C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₃₋₆cycloalkylC₀₋₄alkyl, C₃₋₆cycloalkenylC₀₋₄alkyl, C₁₋₄alkoxyC₀₋₄alkyl,and heterocycloalkylC₀₋₄alkyl, each of which is unsubstituted orsubstituted with one or more groups selected from fluoro, chloro,hydroxy, C₁₋₂alkylS, C₁₋₂alkylS(O), and C₁₋₂alkylS(O)₂, and wherein theheterocycloalkyl is a 3 to 6 membered ring having one or two N, O or Sring atoms.
 7. The compound of claim 1, wherein R₁ is hydrogen and R₂ isselected from the group consisting of hydrogen, methyl, ethyl, n-propyl,allyl, propargyl, 3-fluoro-n-propyl, n-butyl, n-pentyl, iso-propyl,sec-butyl, iso-butyl, 3-methyl-n-butyl, 3,3,3-trifluoro-n-propyl,2,2-difluoroethyl, trifluoromethyl, 1,1-difluoro-n-propyl,2,2,2-trifluoroethyl, 2,2-difluoro-n-but-3-enyl, 4-pentenyl,3,3-difluoro-allyl, 2-methyl-allyl, 3-butenyl, 2-cyanoethyl,3,3-difluoropropyl, 2,2-difluoro-3-butenyl, 2,2-difluoro-n-propyl,4,4,4-trifluorobutyl, C₃₋₆cycloalkyl, oxetan-2-ylmethyl,thietan-2-ylmethyl, 3-fluorocyclobutylmethyl, 3-hydroxycyclobutylmethyl,3-butynyl, methoxymethyl, 2-methoxyethyl, methyl-S(O)₀₋₂C₁₋₂alkyl,3,3-difluorocyclobutylmethyl, oxetan-3-ylmethyl, C₃₋₆cycloalkylmethyl,1-methylcyclopropylmethyl, C₃₋₆cycloalkyl-difluoromethyl,C₃₋₆cycloalkylethyl, thietan-3-ylmethyl, 1-fluorocyclobutylmethyl,1-fluorocyclopropylmethyl, 2,2-difluorocyclopropylmethyl, andcyclopenten-2-ylmethyl.
 8. The compound of claim 1, wherein n is 1, andR⁴ and R⁵ together form a fused ring system selected from:

wherein R¹⁸ is selected from the group consisting of hydrogen, a halogenatom, aryl, trihalomethyl, and C₁₋₄-alkyl.
 9. The compound of claim 1,wherein X is CR⁵R^(5a), R^(5a) is hydrogen, and R⁵ is selected from thegroup consisting of piperidine, phenyl, pyridinyl, pyridinyloxy andpyridinylmethyl, wherein the phenyl and pyridinyl groups may beindependently substituted one or more times with a halogen atom orC₁₋₄-alkyl.
 10. The compound of claim 9, wherein X is CR⁵R^(5a), R^(5a)is hydrogen, and R⁵ is selected from the group consisting of

wherein R²¹ is independently selected from the group consisting ofC₁₋₄-alkyl and aryl.
 11. (canceled)
 12. A compound of claim 1 accordingto the formula:

wherein k₁ and k₂ are 0 or 1 such that a sum of k₁ and k₂ equals 1 or 2;R_(a) is hydrogen, C₁₋₄alkyl, or phenyl; R_(b) is hydrogen, C₁₋₄alkyl,C₁₋₄alkoxy-C₀₋₄alkyl, mono- and di-C₁₋₄alkylaminoC₀₋₄alkyl, mono- anddi-C₁₋₄alkyl carboxamide, C₁₋₄alkanoyl, C₁₋₄alkoxycarbonyl, or phenyl;or two geminal R_(c) substituents, taken in combination form a 3 to 6member spirocyclic ring; R₄ represents 0, 1, or 2 substituents each ofwhich is independently selected from H and C₁₋₄-alkyl; and R₆ ishydrogen or C₁₋₄alkyl.
 13. The compound of claim 1, wherein the divalentresidue:

is selected from the group consisting of:

.
 14. The compound of claim 1, wherein W is selected from the groupconsisting of C(O)—C(O)NH₂, C(O)—C(O)N(H)-cyclopropyl,C(O)-benzothiazole, C(O)-benzoimidazole, C(O)-oxazole, C(O)-imidazole,and C(O)-oxadiazole, wherein the benzothiazole, benzoimidazole, oxazoleand oxadiazole groups may be independently substituted one or more timeswith a halogen atom, aryl, trihalomethyl, C₃₋₆-cycloalkyl or C₁₋₄-alkyl.15. The compound of claim 14, wherein W is selected from the groupconsisting of

wherein R¹⁹ is selected from the group consisting of hydrogen, aryl,trihalomethyl, and C₁₋₄-alkyl.
 16. The compound of claim 1, wherein R²is selected from the group consisting of propyl and (CH₂)₂-cyclobutyl.17. The compound of claim 1, wherein X is CR₅R_(5a), R_(5a) is hydrogenor methyl, and R₅ is a residue selected from the group consisting of:

wherein R₈ is selected from hydrogen, methyl, ethyl, mono-, di-, ortri-fluoromethyl, mono-, di-, or tri-fluoromethoxy, fluoro, and chloro.18. The compound of claim 1, wherein X is CR₅R_(5a); R_(5a) is hydrogenor methyl; R₆ is hydrogen, methyl, ethyl, and mono-, di-, andtri-fluoromethyl; R₅ is a residue selected from the group consisting of:


19. The compound of claim 1, wherein R¹¹ is H and R¹² isC₃₋₆-cycloalkyl.
 20. The compound of claim 1, wherein V is R²⁰ orC(O)—R²⁰, wherein R²⁰ is selected from the group consisting ofC₃₋₆-cycloalkyl, mono- and di-C₁₋₄alkylamino, phenyl, pyrazine,benzooxazole, 4,4-dimethyl-4,5-dihydro-oxazole, benzoimidazole,pyrimidine, benzothiazole 1,1-dioxide and quinazoline, each of which maybe further independently substituted with a halogen atom, CF₃,C₁₋₄-alkyl or C₃₋₆-cycloalkyl.
 21. The compound of claim 1, wherein V isselected from R²⁰ or C(O)R²⁰, wherein R²⁰ is selected from the groupconsisting of

wherein b is 0, 1, or 2; and R₁₈ is selected from the group consistingof hydrogen, a halogen atom, aryl, trihalomethyl, and C₁₋₄-alkyl. 22.The compound of claim 1, wherein X is CR⁵R^(5a), R⁴ and R^(5a) arehydrogen, and R⁵ is aryl-C₀₋₃-alkyl, —O-heterocycle, orheterocycle-C₀₋₃-alkyl, wherein aryl and heterocycle may beindependently substituted one or more times with a halogen atom, aryl,trihalomethyl, C₃₋₆-cycloalkyl or C₁₋₄-alkyl.
 23. The compound of claim1, wherein W is selected from the group consisting of C(O)—C(O)N(R²³)₂,wherein R²³ is independently selected from hydrogen or from the groupconsisting of C₁₋₄-alkyl, C₃₋₆-cycloalkylC₀₋₄alkyl, aryl andheterocycle, each of which may be independently substituted one or moretimes with a halogen atom or C₁₋₄-alkyl. 24-69. (canceled)
 70. A methodof treating HCV infection, liver cirrhosis, chronic liver disease,hepatocellular carcinoma, cryoglobulinaemia, non-Hodgkin's lymphoma,and/or a suppressed innate intracellular immune response in subject inneed thereof comprising administering to the subject a pharmaceuticallyacceptable amount of a compound of claim
 1. 71-73. (canceled)
 74. Apharmaceutical composition comprising a compound of claim 1 and apharmaceutically acceptable excipient.